Thyromimetics for the Treatment of Fatty Liver Diseases

ABSTRACT

The present invention is directed toward the use of thyromimetic compounds that are thyroid receptor ligands, pharmaceutically acceptable salts thereof, and to prodrugs of these compounds for preventing, treating, or ameliorating fatty liver diseases such as steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit, under 35 U.S.C. § 119(e), of theearlier filing date of U.S. Provisional Application No. 60/684,572,filed May 26, 2005, the contents of which is incorporated by referenceherein in its entirety, including figures.

FIELD OF THE INVENTION

The present invention is directed toward the use of thyromimeticcompounds that are thyroid receptor ligands, pharmaceutically acceptablesalts thereof, and to prodrugs of these compounds for preventing,treating, or ameliorating fatty liver diseases such as steatosis,non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

BACKGROUND OF THE INVENTION

The following description of the background is provided to aid inunderstanding, but is not admitted to be, or to describe, prior art. Allpublications and their cited references are incorporated by reference intheir entirety.

Thyroid hormones (TH) are synthesized in the thyroid in response tothyroid stimulating hormone (TSH), which is secreted by the pituitarygland in response to various stimulants (e.g., thyrotropin-releasinghormone (TRH) from the hypothalamus). Thyroid hormones are iodinatedO-aryl tyrosine analogues excreted into the circulation primarily as3,3′,5,5′-tetraiodothyronine (T4). T4 is rapidly deiodinated in localtissues by thyroxine 5′-deiodinase to 3,3′,5′-triiodothyronine (T3),which is the most potent TH. T3 is metabolized to inactive metabolitesvia a variety of pathways, including pathways involving deiodination,glucuronidation, sulfation, deamination, and decarboxylation. Most ofthe circulating T4 and T3 is eliminated through the liver.

THs have profound physiological effects in animals and humans.Hyperthyroidism is associated with increased body temperature, generalnervousness, weight loss despite increased appetite, muscle weakness andfatigue, increased bone resorption and enhanced calcification, and avariety of cardiovascular changes, including increased heart rate,increased stroke volume, increased cardiac index, cardiac hypertrophy,decreased peripheral vascular resistance, and increased pulse pressure.Hypothyroidism is generally associated with the opposite effects.

The biological activity of THs is mediated largely through thyroidhormone receptors (TRs). TRs belong to the nuclear receptor superfamily,which, along with its common partner, the retinoid X receptor, formheterodimers that act as ligand-inducible transcription factors. Likeother nuclear receptors, TRs have a ligand binding domain and a DNAbinding domain and regulate gene expression through ligand-dependentinteractions with DNA response elements (thyroid response elements,TREs). Currently, the literature shows that TRs are encoded by twodistinct genes (TRα and TRβ), which produce several isoforms throughalternative splicing (Williams, Mol. Cell. Biol. 20(22):8329-42 (2000);Nagaya et al., Biochem. Biophys. Res. Commun. 226(2):426-30 (1996)). Themajor isoforms that have so far been identified are TRα-1, TRα-2, TRβ-1and TRβ-2. TRα-1 is ubiquitously expressed in the rat with highestexpression in skeletal muscle and brown fat. TRβ-1 is also ubiquitouslyexpressed with highest expression in the liver, brain and kidney. TRβ-2is expressed in the anterior pituitary gland and specific regions of thehypothalamus as well as the developing brain and inner ear. In the ratand mouse liver, TRβ-1 is the predominant isoform (80%). The TR isoformsfound in human and rat are highly homologous with respect to their aminoacid sequences which suggest that each serves a specialized function.

TSH is an anterior pituitary hormone that regulates thyroid hormoneproduction. TSH formation and secretion is in turn regulated by thehypothalamic TRH. TSH controls the uptake of iodide by the thyroid, thesubsequent release of iodinated thyronines from thyroglobulin (e.g., T3,T4) as well as possibly the intrapituitary conversion of circulating T4to T3. Compounds that mimic T3 and T4 can negatively regulate both TSHand TRH secretion resulting in suppression of TSH levels and decreasedlevels of T3 and other iodinated thyronines. Negative regulation of TSHis postulated based on co-transfection and knockout studies (Abel etal., J. Clin. Invest. 104:291-300 (1999)) to arise through activation ofthe thyroid receptor TRβ, possibly the isoform TRβ-2, which is highlyexpressed in the pituitary.

The most widely recognized effects of THs are an increase in metabolicrate, oxygen consumption and heat production. T3 treatment increasesoxygen consumption in isolated perfused liver and isolated hepatocytes.(Oh et al., J. Nutr. 125(1):112-24 (1995); Oh et al., Proc. Soc. Exp.Biol. Med. 207(3): 260-7 (1994)). Liver mitochondria from hyperthyroidrats exhibit increased oxygen consumption (Carreras et al., Am. J.Physiol. Heart Circ. Physiol. 281(6):H2282-8 (2001)) and higheractivities of enzymes in the oxidative pathways (Dummler et al.,Biochem. J. 317(3):913-8 (1996), Schmehl et al., FEBS Lett.375(3):206-10 (1995), Harper et al., Can. J. Physiol. Pharmacol.72(8):899-908 (1994)). Conversely, mitochondria from hypothyroid ratsshow decreased oxygen consumption. Increased metabolic rates areassociated with increased mitochondrial biogenesis and the associated 2-to 8-fold increase in mitochondrial mRNA levels. Some of the energyproduced from the increased metabolic rate is captured as ATP (adenosine5′-triphosphate), which is stored or used to drive biosynthetic pathways(e.g., gluconeogenesis, lipogenesis, lipoprotein synthesis). Much of theenergy, however, is lost in the form of heat (thermogenesis), which isassociated with an increase in mitochondrial proton leak possiblyarising from TH-mediated effects on mitochondrial membrane, uncouplingproteins, enzymes involved in the inefficient sn-glycerol 3-phosphateshuttle such as mitochondrial sn-glycerol 3-phosphate dehydrogenase(mGPDH), and/or enzymes associated with proton leakage such as theadenine nucleotide transporter (ANT), Na⁺ K⁺-ATPase, Ca²⁺-ATPase and ATPsynthase.

THs also stimulate metabolism of cholesterol to bile acids.Hyperthyroidism leads to decreased plasma cholesterol levels, which islikely due to increased hepatic LDL receptor expression. Hypothyroidismis a well-established cause of hypercholesterolemia and elevated serumLDL. L-T3 is known to lower plasma cholesterol levels. The effects of T3are attributed to TRβ since TRβ-deficient mice are resistant toT3-induced reduction in cholesterol levels. The effects on cholesterollevels have been postulated to result from direct effects on LDLreceptor expression, enzymes involved in conversion of cholesterol tobile acids such as the rate-limiting enzyme cholesterol 7α-hydroxylase(CYP7A) and/or possibly enzymes involved in cholesterol synthesis suchas HMG CoA reductase. In addition, THs are known to affect levels ofother lipoproteins linked to atherosclerosis. THs stimulate apo AI andthe secretion of apo AI in HDL while reducing apo B100. Accordingly, onewould expect T3 and T3 mimetics to inhibit the atherosclerotic processin the cholesterol fed animal.

THs simultaneously increase de novo fatty acid synthesis and oxidationthrough effects on enzymes such as ACC, FAS, and spot-14. THs increasecirculating free fatty acids (FFA) levels in part by increasingproduction of FFAs from adipose tissue via TH-induced lipolysis. Inaddition, T is increase mitochondrial enzyme levels involved in FFAoxidation, e.g., carnitine palmitoyltransferase 1 (CPT-1) and enzymesinvolved in energy storage and consumption.

The liver represents a major target organ of THs. Microarray analysis ofhepatic gene expression from livers of hypothyroid mice and mice treatedwith T3 showed changes in mRNA levels for 55 genes (14 positivelyregulated and 41 negatively regulated) (Feng et al., Mol. Endocrinol.14(7): 947-55 (2000)). Others have estimated that approximately 8% ofthe hepatic genes are regulated by T3. Many of these genes are importantto both fatty acid and cholesterol synthesis and metabolism. T3 is alsoknown to have other effects in liver, including effects on carbohydratesthrough increased glycogenolysis and gluconeogenesis and decreasedinsulin action.

The heart is also a major target organ of THs. THs lower systemicvascular resistance, increase blood volume and produce inotropic andchronotropic effects. Overall TH results in increased cardiac output,which may suggest that T3 or T3 mimetics might be of use to treatpatients with compromised cardiac function (e.g., patients undergoingcoronary artery bypass grafting (CABG) or cardiac arrest) (U.S. Pat. No.5,158,978). The changes in cardiac function are a result of changes incardiac gene expression. Increased protein synthesis and increasedcardiac organ weight are readily observed in T3-treated animals andrepresent the side effect of T3 that limits therapeutic use. TRβknockout mice exhibit high TSH and T4 levels and increased heart ratesuggesting that they retain cardiac sensitivity and therefore that thecardiac effects are via TRα. TRα knockouts exhibit reduced heart rates.

THs also play a role in the development and function of brown and whiteadipose tissue. Both TRα and TRβ are expressed in brown adipose tissue(BAT). THs induce differentiation of white adipose tissue (WAT) as wellas a variety of lipogenic genes, including ACC, FAS, glucose-6-phosphatedehydrogenase and spot-14. Overall, THs play an important role inregulating basal oxygen consumption, fat stores, lipogenesis andlipolysis (Oppenheimer et al., J. Clin. Invest. 87(1):125-32 (1991)).

TH has been used as an antiobesity drug for over 50 years. In the 1940sTH was used alone, whereas in the 1950s it was used in combination withdiuretics and in the 1960s in combination with amphetamines.Hyperthyroidism is associated with increased food intake but is alsoassociated with an overall increase in the basal metabolic rate (BMR).Hyperthyroidism is also associated with decreased body weight (ca. 15%)whereas hypothyroidism is associated with a 25-30% increase in bodyweight. Treating hypothyroidism patients with T3 leads to a decrease inbody weight for most patients but not all (17% of the patients maintainweight).

The effectiveness of TH treatment is complicated by the need forsupraphysiological doses of T3 and the associated side effects, whichinclude cardiac problems, muscle weakness and erosion of body mass.Long-term therapy has also been associated with bone loss. With theseside effects, the medical community has tended to use thyroxine at lowdoses as an adjunct to dietary treatments. At these doses, TH has littleeffect on body weight or BMR.

The effectiveness of T3 to induce weight loss may be attenuated bydefects in TH action. In comparison to normal animals, higher T3 doseswere required in ob/ob mice to affect oxygen consumption, which was onlyobserved in muscle, with no changes in liver and BAT. (Oh et al., J.Nutr. 125(1):112-24 (1995); Oh et al., Proc. Soc. Exp. Biol. Med.207(3):260-7 (1994)). These effects were at least partially attributedto decreased uptake of T3 by the liver.

T3 analogues have been reported. Many were designed for use ascholesterol-lowering agents. Analogues that lower cholesterol andvarious lipoproteins (e.g., LDL cholesterol and Lp(a)) withoutgenerating adverse cardiac effects have been reported (e.g., Underwoodet al., Nature 324:425-9 (1986)). In some cases the improved therapeuticprofile is attributed to increased specificity for the TR-β whereinother cases it may be due to enhanced liver distribution. (Stanton etal., Bioorg. Med. Chem. Lett. 10(15):1661-3 (2000); Dow et al., Bioorg.Med. Chem. Lett. 13(3):379-82 (2003)).

T3 and T3 mimetics are thought to inhibit atherosclerosis by modulatingthe levels of certain lipoproteins known to be independent risk factorsor potential risk factors of atherosclerosis, including low densitylipoprotein (LDL)-cholesterol, high density lipoprotein(HDL)-cholesterol, apoAI, which is a major apoprotein constituent ofhigh density lipoprotein (HDL) particles and lipoprotein (a) or Lp(a).

Lp(a) is an important risk factor, elevated in many patients withpremature atherosclerosis. Lp(a) is considered highly atherogenic (deBruin et al., J. Clin. Endocrinol. Metab. 76:121-126 (1993)). In man,Lp(a) is a hepatic acute phase protein that promotes the binding of LDLto cell surfaces independent of LDL receptors. Accordingly, Lp(a) isthought to provide supplementary cholesterol to certain cells, e.g.,cells involved in inflammation or repair. Lp(a) is an independent riskfactor for premature atherosclerosis. Lp(a) is synthesized in the liver.

Apolipoprotein AI or apoAI is the major component of HDL, which is anindependent risk factor of atherosclerosis. apoAI is thought to promotethe efflux of cholesterol from peripheral tissues and higher levels ofHDL (or apoAI) result in decreased risk of atherosclerosis.

Hyperthyroidism worsens glycemic control in type 2 diabetics. TH therapyis reported to stimulate hepatic gluconeogenesis. Enzymes specific togluconeogenesis and important for controlling the pathway and itsphysiological role of producing glucose are known to be influenced by THtherapy. Phosphoenolpyruvate carboxykinase (PEPCK) is upregulated by TH(Park et al, J. Biol. Chem. 274:211 (1999)) whereas others have foundthat glucose 6-phosphatase is upregulated (Feng et al., Mol.Eildocrinol. 14:947 (2000)). TH therapy is also associated with reducedglycogen levels.

TH therapy results in improved non insulin stimulated and insulinstimulated glucose utilization and decreased insulin resistance in themuscle of ob/ob mice. (Oh et al., J Nutr. 125:125 (1995)).

There is still a need for novel thyromimetics that can be used tomodulate cholesterol levels, to treat obesity, and other metabolicdisorders especially with reduced undesirable effects.

SUMMARY OF THE INVENTION

Fatty acids consist of an alkyl chain with a terminal carboxyl group.Unsaturated fatty acids occur commonly in humans and contain up to sixdouble bonds per chain. Most fatty acids in humans have a length of C16,C18 or C20. Fatty acids are stored primarily as esters of glycerol.Triglycerides (TGs) are triacylglycerols, i.e., where all threehydroxyls are esterified with a fatty acid. In addition to TGs, glycerolesterified with only one fatty acid (monoacylglycerol) or two fattyacids (diacylgycerols, DAGs) are found. The distribution ofesterification sites on glycerol is influenced by many factors and mayhave important biological function. Patty acids are also used in thesynthesis of other molecules, e.g., esters of cholesterol which can bedegraded back to the parent molecule by esterases, and variousphospholipids, including lysophosphatidic acid and phosphatidic acid,which consist of phosphorylated acylated glycerols. Many of theseproducts have biological activity suggesting that modulation of theirlevels may result in beneficial or detrimental effects.

Fatty acids are taken up by the liver from the circulation. Fatty acidsderived from the diet enter the circulation after ingestion and passagethrough the lymphatic system. Once in the circulation the fatty acidsare taken up by tissues and used as a source of energy eitherimmediately or in the future. If not used immediately, the fatty acidsare usually converted to TGs. Subsequently, TGs are hydrolyzed togenerate the free fatty acids and glycerol. Both are often transportedfrom cells such as adipocytes, which store large quantities of TGs, tothe liver. Lipolysis of TGs occurs through the action of lipases. Forexample, lipoprotein lipase hydrolyzes triacylglycerols in plasmalipoproteins. Another example is hormone sensitive lipase (HSL), whichhydrolyzes TGs stored in the adipocyte. HSL is very sensitive to certainhormones, such as insulin which inactivates the enzyme, glucagon,epinephrine, and ACTH.

Fatty acids in the liver are also supplied by de novo synthesis fromsmall molecule intermediates derived from metabolic breakdown of sugars,amino acids and other fatty acids. Accordingly, excess dietary proteinand carbohydrate are readily converted to fatty acids and stored as TGs.A key enzyme in fatty acid synthesis is acetyl-CoA carboxylase, whichcontrols the overall synthesis of fatty acid by controlling thesynthesis of malonyl CoA from acetyl CoA. Fatty acid synthase thencatalyzes the addition of two carbon units to the activated carboxyl endof a growing chain. The result is the fatty acid palmitate. Palmitate isthe precursor fatty acid for nearly all other fatty acids. Enzymes areavailable that lead to unsaturated fatty acids or elongated fatty acids.

Fatty acids are used for energy production primarily through oxidationin mitochondria. The first step entails conversion of the fatty acid toa fatty acyl CoA by acyl-CoA synthetase. Since the oxidizing enzymes arelocated inside the inner mitochondrial membrane and the membrane isimpermeable to CoA and its derivatives, carnitine is used along withcarnitine palmitoyltransferase (CPT) to transfer acyl-CoAs into themitochondria. This step is rate-limiting in fatty acid oxidation. Twocarbon units are removed from the carboxy terminus using fourenzyme-catalyzed reactions. The product is acyl-CoA which can then beused in the synthesis of fatty acids (futile cycling), ketone bodies, orenters the TCA cycle where it is converted to CO₂ and ATP. Some of theenergy generated by fatty acid oxidation is stored as ATP, some used inthe biosynthesis of other molecules, while some is lost in the form ofheat. Agents that increase heat production can enable net energyexpenditure.

Fat accumulation occurs when there is net energy intake relative toenergy expenditure. Energy is often stored as fat, more specificallyTGs. Ideally, fat is stored in the adipocyte which is its naturalstorage site. When in excess, however, fat is stored in other tissues,some of which can be negatively effected. Fat accumulation in the liverwill depend on a multitude of factors, including fatty acid deliveryfrom the circulation, lipogenesis (i.e., de novo lipid synthesis) in theliver, and free fatty acid oxidation.

TH is well known to augment catecholamine stimulation of lipolysis inadipocytes. Adrenergic responsiveness is influenced by the thyroidstatus with clear differences observed in the hypothyroid relative tohyperthyroid states (Bilezikian et al., Endocr. Rev. 4:378-388 (1983);Fisher et al., Biochemistry 6:637-647 (1967); Debons et al., J. LipidRes. 2:86 (1961); Malbon et al., TIPS 9:33-36 (1988)). In thepostabsorptive state, plasma fatty acids are derived mostly fromlipolysis of TGs in adipose tissue. Hyperthyroidism is known to enhancethis process. T4 is reported to cause a diminution of lipoprotein lipaseactivity in the mammary gland and adipose tissue (Del Prado et al.,Biochem. J. 301:495-501 (1994)). A decrease in lipoprotein lipaseactivity in the peripheral tissues was postulated to contribute to thehigher TGs found in the serum of chronic hyperthyroid rats.

Total splanchnic uptake of fatty acids is increased in hyperthyroidpatients. This is thought to arise from fatty acid blood concentrationas well as augmented splanchnic blood flow. The latter would be expectedas a means to compensate for the increased metabolic demand of the liverin the hyperthyroid state (Heimberg et al., Endocrine Rev. 6:590(1985)).

TH is known to increase the expression of genes encoding for lipogenicenzymes and proteins closely related to lipogenesis such as hepatic S14.S14 protein is known to regulate the transcription of lipogenic genes.Hepatic fatty acid synthase (FAS) is another gene important forlipogenesis. TREs are associated with the FAS gene and TH is known topositively regulate transcription of FAS. Acetyl CoA carboxylase (ACC)is also increased with TH. Fatty acid production is increased in rodentswith elevated TH levels (Roncari et al., J. Biol. Chem. 250:4134-4138(1975)).

TH increases fatty acid oxidation. Hyperthyroidism is associated with anincrease in basal metabolic rate and correspondingly higher energydemand. Hypothyroidism is associated with decreased metabolic rate. Inthe hyperthyroid state, the major fuel is fatty acids since thehyperthyroid mammal is thought to have limited capacity for conservationof carbohydrate as glycogen. Increased oxidation of fatty acids leads toincreased production of the products of fatty acid oxidation, i.e., CO₂and ketone bodies in the hyperthyroid state. The rate-limiting enzyme infatty acid oxidation is CPT-1. CPT-1 expression appears to be controlledby TH based on the discovery of a TRE in the CPT-1 promoter region(Barrero et al., Biochem. Biophys. Res. Comm., 279:81-88 (2000)).Moreover, hypothyroidism decreases CPT-1 expression and hyperthyroidismresults in an increase.

TH is thought to increase mitochondrial enzyme activity. This couldoccur by increased expression in certain genes in the mitochondria or byincreased mitochondria. Increases in mitochondria and/or mitochondrialenzymes associated with thermogenesis such as glycerol-3-phosphatedehydrogenase, cytochrome C oxidase, ATPases and possibly uncouplingproteins (e.g., UCP2) could result in increased fatty acid oxidation andnet energy expenditure. While the liver is not the organ most commonlycited in the literature for the effect of TH on energy expenditure andthermogenesis (usually fat and muscle), it is a highly metabolic organwith a capacity for oxidizing free fatty acids. Furthermore, the liveris relatively inefficient in its ability to capture the energy producedfrom FFA oxidation in the form of ATP. Consequently, the liver is arelatively thermogenic organ. THs are known to increase hepatic CPT-1and mitochondrial GPDH activities.

TH results in increased hepatic lipogenesis and increased fatty aciddelivery to the liver from the periphery as a result of enhancedlipolysis.

Simultaneously, TH increases fatty acid oxidation. Fat accumulation inthe liver would likely depend on the contribution of each component. Itis known that thyrotoxic patients are characterized by some degree offatty infiltration into liver and by cytoplasmic vacuolization, nuclearirregularity, and hyperchromatism in hepatocytes (Donner et al., Arch.Intern. Med., 120:25-32 (1967); Klion et al., Am. J. Med. 50:317-324(1971)). Liver fat accumulation can be associated with liver toxicitywhich could arise from direct or indirect effects of TH, e.g.,accumulation of fat is associated with liver toxicity.

Severe hyperthyroidism, thyrotoxicosis, is associated with a variety ofabnormalities of liver function which are thought to be related tomitochondrial dysfunction. Extensive DNA fragmentation and increasedcaspase-3 activity and caspase-9 activity were observed along with adecrease in the number or cristae (Upadhyay et al., Hepatology,39:1120-1130 (2004)). In some cases liver function is reported to becompromised 45% to 90%. Ultrastructural and functional changes in themitochondria, such as enlargement, mass increase, and formation ofmegamitochondria have been reported in the liver of hyperthyroidpatients.

TH is known to induce hyperphagia which results in an increasedconsumption of calories. The increased consumption of both fats as wellas carbohydrates and proteins results in conversion to fatty acids andin increased fat stores if not compensated by an equal or greaterincrease in energy expenditure.

TH is associated with a reduction in total fat pool and weight loss.Reduction in the pool is thought to be due to an enhanced activity ofthe hormone sensitive lipase in adipose tissue. While the pool maydecrease and fat content in the periphery may decrease, FFAs producedfrom enhanced lipolysis could result in the accumulation of fat in theliver. In one study, thyroxine treatment is reported to decrease liverTG 5-fold after one week but rebound 4-fold by the end of five weeks oftreatment (Varas et al., Horm. Metab. Res. 31:514-518 (1999)).

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological termthat encompasses a disease spectrum ranging from simple TG accumulationin hepatocytes to hepatic steatosis with inflammation (nonalcoholicsteatohepatitis, NASH) to fibrosis and cirrhosis. NAFLD is the mostfrequent cause of liver enzyme elevations. The prevalence of NAFLD inthe population is estimated to be 14-28%. Hepatic insulin resistance isassociated with hepatic steatosis.

Products from TG metabolism, e.g., DAGs and long chain AcylCoAs (LCACOA)are thought to negatively effect insulin response through effects on theinsulin receptor phosphorylation. Long chain CoAs and DAG increaseSer/Thr phosphorylation of insulin receptor substrates (IRS1-3) andthereby disrupt Tyr phosphorylation of these substrates by the insulinreceptor. The resulting hepatic insulin resistance contributes to thedevelopment of compensatory hyperinsulinemia which further drives fataccumulation via SREBP1. Reduction in TGs may reduce the levels of DAGsand LCACoAs and therefore improve the response to insulin. Improvedresponse to insulin may also diminish further fat accumulation.

Oxidative stress results from an imbalance between pro-oxidant andantioxidant chemical species that leads to oxidative damage. Oxidationof fatty acids is an important source of reactive oxygen species (ROS).Some of the consequences of increased ROS is depleted ATP, destructionof membranes via lipid peroxidation, and release of proinflammatorycytokines. An increase in liver triglycerides may lead to increasedoxidative stress in the hepatocytes, and the progression of hepaticsteatosis to NASH. Human livers with NASH have increased lipidperoxidation and impaired mitochondrial function. This can result incell death, hepatic stellate cell activation and fibrosis andinflammation. All of these activities may cause patients with NAFLD tobe at risk for NASH, a more serious disease with higher risk of livercirrhosis and hepatocellular carcinoma. TH is known to increase fattyacid oxidation and mitochondrial enzyme activity which could result inincreased ROS and liver damage. Prodrugs that are activated by P450s mayalso cause an increase in ROS.

Thus, it was unknown whether delivery of a thyroid mimetic would resultin liver damage and an increase in fat content. It was also unknownwhether a non-liver toxic thyromimetic could reduce liver fat or whetherit could reduce liver fat in a sustained manner or whether it couldreduce liver fat without adverse effects on the cardiovascular system,adverse effects on the thyroid axis, mitochondrial function, reductionsin whole body fat, reductions in serum free fatty acids or withouteither muscle wasting or bone loss. Prior to the discoveries of thepresent invention, the effects of thyroid hormone agonists on fathomeostasis have been focused on modulation of whole body weight. Therehave been no studies reporting the effects of thyroid hormone on liverfat content, but many studies have reported decreases in body weightfollowing treatment with either a natural or synthetic thyroid hormoneagonist. Lastly, it was unclear whether reduction in fat would occur andultimately be beneficial toward preventing or treating liver diseasesassociated with NAFLD, including liver cirrhosis, liver cancer, anddiseases associated with hepatic insulin resistance, such as diabetes.

Prior to the discoveries of the present invention it was unexpected thata synthetic thyroid hormone would produce effects in the liver, e.g.,decreases in hepatic fat content measured either chemically orhistologically, that are not produced by the naturally occurring ligand,T3.

-   -   1. T3 has not been reported to decrease liver fat in a sustained        manner (as measured by chemical or histologic means) and without        negative effects on the heart or thyroid axis; although T3 is        known to increase metabolic rate and decrease body weight.    -   2. synthetic thyroid agonists have not been reported to decrease        hepatic steatosis, although some thyromimetics have been shown        to increase metabolic rate and decrease body weight.

Thus, it was unexpected when the present Inventors discovered that thesynthetic thyroid hormone agonists TRIAC, Compound 17, Compound 7, andCompound 6 all demonstrated a significant decrease in hepatictriglyceride content following systemic administration of the compounds,while T3 did not demonstrate a decrease in hepatic triglyceride content.TRIAC, Compound 17 and T3, however, decreased body weight, whileCompound 7 and Compound 6 did not decrease body weight.

Further, surprisingly the present Inventors discovered that oraladministration of Compound cis-13-1 decreased hepatic steatosis measuredboth chemically and histologically in ob/ob mice while T3 had nosignificant effect on hepatic steatosis in ob/ob mice. Compound cis-13-1had no effect on epididymal fat pad weight, while T3 significantlydecreased epididymal fat pad weight, consistent with induction oflipolysis following T3 administration.

Further, surprisingly the present Inventors discovered that oraladministration of Compounds cis-13-1 and 18 decreased hepatic steatosismeasured histologically in ZDF rats.

Further, surprisingly the present Inventors discovered that oraladministration of Compound cis-13-1 decreased hepatic steatosis measuredhistologically DIO mice.

Further, surprisingly liver triglyceride levels were reduced aftertreatment with thyromimetics of the present invention for 10 weeks inthe DIO mouse, for 9 weeks in the ob/ob mouse, and after one week in thenormal Sprague-Dawley rat. Administration of thyromimetics led toimproved liver histology in the ob/ob mouse, the DIO mouse and the ZDFrat and led to improved mitochondrial morphology after 10 weeks oftreatment in the DIO mouse. In some models, reduced liver fat led toreduced liver enzymes (e.g., ob/ob mice treated for 9 weeks).

Therefore, surprisingly the present Inventors discovered that syntheticthyroid agonists, such as TRIAC and Compounds 7, 18, 6, 17, and cis-13-1decreased hepatic steatosis, measured either histologically orchemically, while T3 did not decrease hepatic steatosis, measured eitherhistologically or chemically. However, in the models tested, T3 and thereported synthetic thyroid agonists Compound 18, Compound 17 and TRIACdid decrease body weight and/or peripheral fat content as previouslyreported. Since the natural ligand, T3, did not produce a decrease inhepatic steatosis, measured either histologically or chemically, butretained the extrahepatic effects of weight loss or loss of peripheralfat mass, it is completely unexpected that synthetic thyroid agonistswould decrease hepatic fat content. The loss of hepatic fat was observedwith either previously investigated synthetic thyroid agonists, or novelphosphorous containing thyroid agonists.

The present invention relates to the use of thyromimetic compounds inmethods of decreasing fat content in the liver of an animal comprisingadministering to said animal a therapeutically effective amount of athyromimetic compound, a pharmaceutically acceptable salt thereof, orprodrugs thereof or pharmaceutically acceptable salts of said prodrugs.The invention further relates to methods of preventing, treating, orameliorating fatty liver disease in an animal comprising administeringto said animal a therapeutically effective amount of a thyromimeticcompound, a pharmaceutically acceptable salt thereof, or prodrugsthereof or pharmaceutically acceptable salts of said prodrugs. Thethyromimetic compounds bind to thyroid receptors in the liver.Activation of these receptors results in modulation of gene expressionof genes regulated by thyroid hormones. In one aspect, the thyromimeticcompounds used in the method of the invention are useful for improvingefficacy, improving the therapeutic index, e.g., decreasing non-liverrelated toxicities and side effects, or for improving liver selectivity,i.e., increasing distribution of an active drug to the liver relative toextrahepatic tissues and more specifically increasing distribution of anactive drug to the nucleus of liver cells relative to the nucleus ofextrahepatic tissue cells (including heart, kidney and pituitary).Prodrugs of the compounds are useful for increasing oral bioavailabilityand sustained delivery of the thyromimetics.

In another aspect, the present invention relates to the use of compoundsof Formula I-IX. The compounds of Formula I-IX may be an active form ora prodrug thereof. Further included in the present invention is the useof pharmaceutically acceptable salts, including but not limited to acidaddition salts and physiological salts, and co-crystals of saidcompounds of Formula I-IX. Further included in the present invention isthe use of prodrugs of compounds of Formula I-IX that are active forms,and pharmaceutically acceptable salts, including but not limited to acidaddition salts and physiological salts, and co-crystals thereof.

Some of the compounds of Formula I-IX have asymmetric centers. Thus,included in the present invention is the use of racemic mixtures,enantiomerically enriched mixtures, diastereomeric mixtures, includingdiastereomeric enriched mixtures, and individual stereoisomers of thecompounds of Formula I-IX and prodrugs thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows hematoxylin and eosin (H & E) stained sections of liverfrom an ob/ob mouse rat treated with vehicle, T3 (100 nmole/kg/d), orCompound cis-13-1 (30 mg/kg/d).

FIG. 2A shows an H & E stained section of liver from a ZDF rat treatedwith vehicle.

FIG. 2B shows an H & E stained section of liver from a ZDF rat treatedwith Compound cis-13-1 (0.2 mg/kg/d).

FIG. 2C shows an H & E stained section of liver from a ZDF rat treatedwith Compound cis-13-1 (1 mg/kg/d).

FIG. 2D shows an H & E stained section of liver from a ZDF rat treatedwith Compound cis-13-1 (2.5 mg/kg/d).

FIG. 3A shows an H & E stained section of liver from a DIO mouse treatedwith vehicle.

FIG. 3B shows an H & E stained section of liver from a DIO mouse treatedwith Compound cis-13-1 (30 mg/kg/d).

DEFINITIONS

As used herein, the following terms are defined with the followingmeanings, unless explicitly stated otherwise.

T groups that have more than one atom are read from left to rightwherein the left atom of the T group is connected to the phenyl groupbearing the R¹ and R² groups, and the right atom of the T group islinked to the carbon, phosphorus, or other atom in X or E. For example,when T is —O—CH₂— or —N(H)C(O)— it means -phenyl-O—CH₂—X and-phenyl-N(H)C(O)—X.

The term “alkyl” refers to a straight or branched or cyclic chainhydrocarbon radical with only single carbon-carbon bonds. Representativeexamples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, andcyclohexyl, all of which may be optionally substituted. Alkyl groups areC₁-C₂₀.

The term “aryl” refers to aromatic groups which have 5-14 ring atoms andat least one ring having a conjugated pi electron system and includescarbocyclic aryl, heterocyclic aryl and biaryl groups, all of which maybe optionally substituted.

Carbocyclic aryl groups are groups which have 6-14 ring atoms whereinthe ring atoms on the aromatic ring are carbon atoms. Carbocyclic arylgroups include monocyclic carbocyclic aryl groups and polycyclic orfused compounds such as optionally substituted naphthyl groups.

Heterocyclic aryl or heteroaryl groups are groups which have 5-14 ringatoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring andthe remainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude oxygen, sulfur, nitrogen, and selenium. Suitable heteroarylgroups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and thelike, all optionally substituted.

The term “biaryl” represents aryl groups which have 5-14 atomscontaining more than one aromatic ring including both fused ring systemsand aryl groups substituted with other aryl groups. Such groups may beoptionally substituted. Suitable biaryl groups include naphthyl andbiphenyl.

The term “optionally substituted” or “substituted” includes groupssubstituted by one, two, three, four, five, or six substituents,independently selected from lower alkyl, lower aryl, lower aralkyl,lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, loweraryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy,lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, loweralkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl,-carboxamido, nitro, lower acyloxy, lower aminoalkyl, loweralkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, loweralkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl,lower-carboxamidoalkylaryl, lower-carboxamidoaryl, lower hydroxyalkyl,lower haloalkyl, lower alkylaminoalkylcarboxy-, loweraminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl,and lower arylalkyloxyalkyl.

“Substituted aryl” and “substituted heteroaryl” refers to aryl andheteroaryl groups substituted with 1-3 substituents. These substituentsare selected from the group consisting of lower alkyl, lower alkoxy,lower perhaloalkyl, halo, hydroxy, and amino.

The term “-aralkyl” refers to an alkylene group substituted with an arylgroup. Suitable aralkyl groups include benzyl, picolyl, and the like,and may be optionally substituted. “Heteroarylalkyl” refers to analkylene group substituted with a heteroaryl group.

The term “alkylaryl-” refers to an aryl group substituted with an alkylgroup. “Lower alkylaryl-” refers to such groups where alkyl is loweralkyl.

The term “lower” referred to herein in connection with organic radicalsor compounds respectively refers to 6 carbon atoms or less. Such groupsmay be straight chain, branched, or cyclic.

The term “higher” referred to herein in connection with organic radicalsor compounds respectively refers to 7 or more carbon atoms. Such groupsmay be straight chain, branched, or cyclic.

The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that arecyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbonatoms Suitable cyclic groups include norbornyl and cyclopropyl. Suchgroups may be substituted.

The term “heterocyclic,” “heterocyclic alkyl” or “heterocycloalkyl”refer to cyclic groups of 3 to 10 atoms, and in one aspect are 3 to 6atoms, containing at least one heteroatom, in a further aspect are 1 to3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, andnitrogen. Heterocyclic groups may be attached through a nitrogen orthrough a carbon atom in the ring. The heterocyclic alkyl groups includeunsaturated cyclic, fused cyclic and spirocyclic groups. Suitableheterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl,and pyridyl.

The terms “arylamino” (a), and “aralkylamino” (b), respectively, referto the group —NRR′ wherein respectively, (a) R is aryl and R′ ishydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R′ isaralkyl and R′ is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.

The term “acyl” refers to —C(O)R where R is alkyl, heterocycloalkyl, oraryl.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl,aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.

The term “carboxyl” refers to —C(O)OH.

The term “oxo” refers to ═O in an alkyl or heterocycloalkyl group.

The term “amino” refers to —NRR′ where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, allexcept H are optionally substituted; and R and R′ can form a cyclic ringsystem.

The term “-carboxylamido” refers to —CONR₂ where each R is independentlyhydrogen or alkyl.

The term “-sulphonylamido” or “-sulfonylamido” refers to —S(═O)₂NR₂where each R is independently hydrogen or alkyl.

The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.

The term “alkylaminoalkylcarboxy” refers to the groupalkyl-NR-alk-C(O)—O— where “alk” is an alkylene group, and R is a H orlower alkyl.

The term “sulphonyl” or “sulfonyl” refers to —SO₂R, where R is H, alkyl,aryl, aralkyl, or heterocycloalkyl.

The term “sulphonate” or “sulfonate” refers to —SO₂OR, where R is —H,alkyl, aryl, aralkyl, or heterocycloalkyl.

The term “alkenyl” refers to unsaturated groups which have 2 to 12 atomsand contain at least one carbon-carbon double bond and includesstraight-chain, branched-chain and cyclic groups. Alkenyl groups may beoptionally substituted. Suitable alkenyl groups include allyl.“1-Alkenyl” refers to alkenyl groups where the double bond is betweenthe first and second carbon atom. If the 1-alkenyl group is attached toanother group, e.g., it is a W substituent attached to the cyclicphosphonate, it is attached at the first carbon.

The term “alkynyl” refers to unsaturated groups which have 2 to 12 atomsand contain at least one carbon-carbon triple bond and includesstraight-chain, branched-chain and cyclic groups. Alkynyl groups may beoptionally substituted. Suitable alkynyl groups include ethynyl.“1-Alkynyl” refers to alkynyl groups where the triple bond is betweenthe first and second carbon atom. If the 1-alkynyl group is attached toanother group, e.g., it is a W substituent attached to the cyclicphosphonate, it is attached at the first carbon.

The term “alkylene” refers to a divalent straight chain, branched chainor cyclic saturated aliphatic group. In one aspect the alkylene groupcontains up to and including 10 atoms. In another aspect the alkylenegroup contains up to and including 6 atoms. In a further aspect thealkylene group contains up to and including 4 atoms. The alkylene groupcan be either straight, branched or cyclic.

The term “acyloxy” refers to the ester group —O—C(O)R, where R is H,alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

The term “aminoalkyl-” refers to the group NR₂-alk- wherein “alk” is analkylene group and R is selected from —H, alkyl, aryl, aralkyl, andheterocycloalkyl.

The term “alkylaminoalkyl-” refers to the group alkyl-NR-alk- whereineach “alk” is an independently selected alkylene, and R is H or loweralkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and thealkylene group is lower alkyl and alkylene, respectively.

The term “arylaminoalkyl-” refers to the group aryl-NR-alk- wherein“alk” is an alkylene group and R is —H, alkyl, aryl, aralkyl, orheterocycloalkyl. In “lower arylaminoalkyl-,” the alkylene group islower alkylene.

The term “alkylaminoaryl-” refers to the group alkyl-NR-aryl- wherein“aryl” is a divalent group and R is —H, alkyl, aralkyl, orheterocycloalkyl. In “lower alkylaminoaryl-,” the alkyl group is loweralkyl.

The term “alkoxyaryl-” refers to an aryl group substituted with analkyloxy group. In “lower alkyloxyaryl-,” the alkyl group is loweralkyl.

The term “aryloxyalkyl-” refers to an alkyl group substituted with anaryloxy group.

The term “aralkyloxyalkyl-” refers to the group aryl-alk-O-alk- wherein“alk” is an alkylene group. “Lower aralkyloxyalkyl-” refers to suchgroups where the alkylene groups are lower alkylene.

The term “alkoxy-” or “alkyloxy-” refers to the group alkyl-O—.

The term “alkoxyalkyl-” or “alkyloxyalkyl-” refer to the groupalkyl-O-alk- wherein “alk” is an alkylene group. In “loweralkoxyalkyl-,” each alkyl and alkylene is lower alkyl and alkylene,respectively.

The term “alkylthio-” refers to the group alkyl-S—.

The term “alkylthioalkyl-” refers to the group alkyl-5-alk- wherein“alk” is an alkylene group. In “lower alkylthioalkyl-,” each alkyl andalkylene is lower alkyl and alkylene, respectively.

The term “alkoxycarbonyloxy-” refers to alkyl-O—C(O)—O—.

The term “aryloxycarbonyloxy-” refers to aryl-O—C(O)—O—.

The term “alkylthiocarbonyloxy-” refers to alkyl-S—C(O)—O—.

The term “amido” refers to the NR₂ group next to an acyl or sulfonylgroup as in NR₂—C(O)—, RC(O)—NR¹—, NR₂—S(═O)₂— and RS(═O)₂—NR¹—, where Rand R¹ include —H, alkyl, aryl, aralkyl, and heterocycloalkyl.

The term “carboxamido” refer to NR₂—C(O)— and RC(O)—NR¹—, where R and R¹include —H, alkyl, aryl, aralkyl, and heterocycloalkyl. The tern doesnot include urea, —NR—C(O)—NR—.

The terms “sulphonamido” or “sulfonamido” refer to NR₂—S(═O)₂— andRS(═O)₂—NR¹—, where R and R¹ include —H, alkyl, aryl, aralkyl, andheterocycloalkyl. The term does not include sulfonylurea,—NR—S(═O)₂—NR—.

The term “carboxamidoalkylaryl” and “carboxamidoaryl” refers to anaryl-alk-NR¹—C(O), and ar-NR¹—C(O)-alk-, respectively where “ar” isaryl, “alk” is alkylene, R¹ and R include H, alkyl, aryl, aralkyl, andheterocycloalkyl.

The term “sulfonamidoalkylaryl” and “sulfonamidoaryl” refers to anaryl-alk-NR¹—S(═O)₂—, and ar-NR¹—S(═O)₂—, respectively where “ar” isaryl, “alk” is alkylene, R¹ and R include —H, alkyl, aryl, aralkyl, andheterocycloalkyl.

The term “hydroxyalkyl” refers to an alkyl group substituted with one—OH.

The term “haloalkyl” refers to an alkyl group substituted with halo.

The term “cyano” refers to —C≡N.

The term “nitro” refers to —NO₂.

The term “acylalkyl” refers to an alkyl-C(O)-alk-, where “alk” isalkylene.

The term “aminocarboxamidoalkyl-” refers to the group NR₂—C(O)—N(R)-alk-wherein R is an alkyl group or H and “alk” is an alkylene group. “Loweraminocarboxamidoalkyl-” refers to such groups wherein “alk” is loweralkylene.

The term “heteroarylalkyl” refers to an alkylene group substituted witha heteroaryl group.

The term “perhalo” refers to groups wherein every C—H bond has beenreplaced with a C-halo bond on an aliphatic or aryl group. Suitableperhaloalkyl groups include —CF₃ and —CFCl₂.

The term “co-crystal” as used herein means a crystalline materialcomprised of two or more unique solids at room temperature, eachcontaining distinctive physical characteristics, such as structure,melting point and heats of fusion. The co-crystals of the presentinvention comprise a co-crystal former H-bonded to a compound of thepresent invention. The co-crystal former may be H-bonded directly to thecompound of the present invention or may be H-bonded to an additionalmolecule which is bound to the compound of the present invention. Theadditional molecule may be H-bonded to the compound of the presentinvention or bound ionically to the compound of the present invention.The additional molecule could also be a second API. Solvates ofcompounds of the present invention that do not further comprise aco-crystal former are not “co-crystals” according to the presentinvention. The co-crystals may however, include one or more solvatemolecules in the crystalline lattice. That is, solvates of co-crystals,or a co-crystal further comprising a solvent or compound that is aliquid at room temperature, is included in the present invention as aco-crystal.

The co-crystals may also be a co-crystal between a co-crystal former anda salt of a compound of the present invention, but the compound of thepresent invention and the co-crystal former are constructed or bondedtogether through hydrogen bonds. Other modes of molecular recognitionmay also be present including, pi-stacking, guest-host complexation andvan der Waals interactions. Of the interactions listed above,hydrogen-bonding is the dominant interaction in the formation of theco-crystal, (and a required interaction according to the presentinvention) whereby a non-covalent bond is formed between a hydrogen bonddonor of one of the moieties and a hydrogen bond acceptor of the other.

Crystalline material comprised of solid compound of the presentinvention and one or more liquid solvents (at room temperature) areincluded in the present invention as “solvates.” A “hydrate” is wherethe solvent is water. Other forms of the present invention include, butare not limited to, anhydrous forms and de-solvated solvates.

The ratio of the compound of the present invention to co-crystal formeror solvent may be specified as stoichiometric or non-stoichiometric.1:1, 1.5:1, 1:1.5, 2:1, 1:2, and 1:3 ratios of API:co-crystalformer/solvent are examples of stoichiometric ratios.

The term “binding” means the specific association of the compound ofinterest to the thyroid hormone receptor. One method of measuringbinding in this invention is the ability of the compound to inhibit theassociation of ¹²⁵I-T3 with a mixture of thyroid hormone receptors usingnuclear extracts or purified or partially purified thyroid hormonereceptor (for example, alpha or beta) in a heterologous assay.

The term “energy expenditure” means basal or resting metabolic rate asdefined by Schoeller et al., J Appl Physiol. 53(4):955-9 (1982).Increases in the resting metabolic rate can also be measured usingincreases in O₂ consumption and/or CO₂ efflux and/or increases in organor body temperature.

The phrase “therapeutically effective amount” means an amount of acompound or a combination of compounds that ameliorates, attenuates oreliminates one or more of the symptoms of a particular disease orcondition or prevents, modifies, or delays the onset of one or more ofthe symptoms of a particular disease or condition.

The term “pharmaceutically acceptable salt” includes salts of compoundsof Formula I and its prodrugs derived from the combination of a compoundof this invention and an organic or inorganic acid or base. Suitableacids include acetic acid, adipic acid, benzenesulfonic acid,(+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid,citric acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaricacid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid,hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonicacid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid,methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid,nitric acid, oleic acid,4,4′-methylenebis[3-hydroxy-2-naphthalenecarboxylic acid], phosphoricacid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid,sulfosalicylic acid, tannic acid, tartaric acid, terphthalic acid, andp-toluenesulfonic acid.

The term “patient” means an animal.

The term “animal” includes birds and mammals. In one embodiment a mammalincludes a dog, cat, cow, horse, goat, sheep, pig or human. In oneembodiment the animal is a human. In another embodiment the animal is amale. In another embodiment the animal is a female.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates a biologically activecompound as a result of spontaneous chemical reaction(s), enzymecatalyzed chemical reaction(s), and/or metabolic chemical reaction(s),or a combination of each. Standard prodrugs are formed using groupsattached to functionality, e.g., HO—, HS—, HOOC—, R₂N—, associated withthe drug, that cleave in vivo. Standard prodrugs include but are notlimited to carboxylate esters where the group is alkyl, aryl, aralkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl,thiol and amines where the group attached is an acyl group, analkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groupsillustrated are exemplary, not exhaustive, and one skilled in the artcould prepare other known varieties of prodrugs. Such prodrugs of thecompounds of the present invention fall within this scope. Prodrugs mustundergo some form of a chemical transformation to produce the compoundthat is biologically active or is a precursor of the biologically activecompound. In some cases, the prodrug is biologically active, usuallyless than the drug itself, and serves to improve drug efficacy or safetythrough improved oral bioavailability, and/or pharmacodynamic half-life,etc. Prodrug forms of compounds may be utilized, for example, to improvebioavailability, improve subject acceptability such as by masking orreducing unpleasant characteristics such as bitter taste orgastrointestinal irritability, alter solubility such as for intravenoususe, provide for prolonged or sustained release or delivery, improveease of formulation, or provide site-specific delivery of the compound.Prodrugs are described in The Organic Chemistry of Drug Design and DrugAction, by Richard B. Silverman, Academic Press, San Diego, 1992.Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352-401; Design ofProdrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985;Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed.by E. B. Roche, American Pharmaceutical Association, Washington, 1977;and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford, 1980.

Prodrugs of carboxylic acid-containing thyromimetics are convertible bysolvolysis or under physiological conditions to the free carboxylicacids. Examples of prodrugs include carboxylic acid esters, and arepreferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, aryl esters, mono- or di-substituted lower alkyl esters,e.g., the ω-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, and the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxy-methyl ester.

Prodrugs of phosphorus-containing thyromimetics breakdown chemically orenzymatically to a phosphonic acid or phosphinic acid group or amonoester thereof in vivo. As employed herein the term includes, but isnot limited to, the following groups and combinations of these groups:

Acyloxyalkyl esters which are well described in the literature (Farquharet al., J. Pharm. Sci. 72:324-325 (1983)).

Other acyloxyalkyl esters are possible in which a cyclic alkyl ring isformed. These esters have been shown to generate phosphorus-containingnucleotides inside cells through a postulated sequence of reactionsbeginning with deesterification and followed by a series of eliminationreactions (e.g., Freed et al., Biochem. Pharm, 38:3193-3198 (1989)).

Another class of these double esters known as alkyloxycarbonyloxymethylesters, as shown in formula A, where R is alkoxy, aryloxy, alkylthio,arylthio, alkylamino, and arylamino; R′, and R″ are independently —H,alkyl, aryl, alkylaryl, and heterocycloalkyl have been studied in thearea of β-lactam antibiotics (Nishimura et al., J. Antibiotics40(1):81-90 (1987); for a review see Ferres, H., Drugs of Today, 19:499(1983)). More recently Cathy, M. S. et al. (Abstract from AAPS WesternRegional Meeting, April, 1997) showed that thesealkyloxycarbonyloxymethyl ester prodrugs on(9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to30% in dogs.

wherein R, R′, and R″ are independently H, alkyl, aryl, alkylaryl, andalicyclic (see WO 90/08155; WO 90/10636).

Other acyloxyalkyl esters are possible in which a cyclic alkyl ring isformed such as shown in formula B. These esters have been shown togenerate phosphorus-containing nucleotides inside cells through apostulated sequence of reactions beginning with deesterification andfollowed by a series of elimination reactions (e.g., Freed et al.,Biochem. Pharm. 38:3193-3198 (1989)).

wherein R is —H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio,arylthio, alkylamino, arylamino, or cycloalkyl.

Aryl esters have also been used as phosphonate prodrugs (e.g., DeLambertet al., J. Med. Chem. 37(7):498-511 (1994); Serafinowska et al., J. Med.Chem. 38(8):1372-9 (1995). Phenyl as well as mono and poly-substitutedphenyl proesters have generated the parent phosphonic acid in studiesconducted in animals and in man (Formula C). Another approach has beendescribed where Y is a carboxylic ester ortho to the phosphate (Khamneiet al., J. Med. Chem. 39:4109-15 (1996)).

wherein Y is —H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen,amino, alkoxycarbonyl, hydroxy, cyano, and heterocycloalkyl.

Benzyl esters have also been reported to generate the parent phosphonicacid. In some cases, using substituents at the para-position canaccelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxygroup [Formula D, X═—H, OR or O(CO)R or O(CO)OR] can generate the4-hydroxy compound more readily through the action of enzymes, e.g.,oxidases, esterases, etc. Examples of this class of prodrugs aredescribed in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992);WO 91/19721.

wherein X and Y are independently —H, alkyl, aryl, alkylaryl, alkoxy,acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl;and R′ and R″ are independently —H, alkyl, aryl, alkylaryl, halogen, andcyclic alkyl.

Thio-containing phosphonate proesters may also be useful in the deliveryof drugs to hepatocytes. These proesters contain a protected thioethylmoiety as shown in formula E. One or more of the oxygens of thephosphonate can be esterified. Since the mechanism that results inde-esterification requires the generation of a free thiolate, a varietyof thiol protecting groups are possible. For example, the disulfide isreduced by a reductase-mediated process (Puech et al., Antiviral Res.22:155-174 (1993)). Thioesters will also generate free thiolates afteresterase-mediated hydrolysis Benzaria, et al., J. Med. Chem.39(25):4958-65 (1996)). Cyclic analogs are also possible and were shownto liberate phosphonate in isolated rat hepatocytes. The cyclicdisulfide shown below has not been previously described and is novel.

wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,aryloxycarbonyl, or alkylthio.

Other examples of suitable prodrugs include proester classes exemplifiedby Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al., J.Med. Chem. 38(8):1372-9 (1995); Starrett et al., J. Med. Chem. 37:1857(1994); Martin et al. J. Pharm. Sci. 76:180 (1987); Alexander et al.,Collect. Czech. Chem. Commun. 59:1853 (1994); and EP 0 632 048 A1. Someof the structural classes described are optionally substituted,including fused lactones attached at the omega position (formulae E-1and E-2) and optionally substituted 2-oxo-1,3-dioxolenes attachedthrough a methylene to the phosphorus oxygen (formula E-3) such as:

wherein R is —H, alkyl, cycloalkyl, or heterocycloalkyl; andwherein Y is —H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy,halogen, amino, heterocycloalkyl, and alkoxycarbonyl.

The prodrugs of Formula E-3 are an example of “optionally substitutedheterocycloalkyl where the cyclic moiety contains a carbonate orthiocarbonate.”

Propyl phosphonate proesters can also be used to deliver-drugs intohepatocytes. These proesters may contain a hydroxyl and hydroxyl groupderivatives at the 3-position of the propyl group as shown in formula F.The R and X groups can form a cyclic ring system as shown in formula F.One or more of the oxygens of the phosphonate can be esterified.

wherein R is alkyl, aryl, heteroaryl;X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; andY is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen,hydrogen, hydroxy, acyloxy, amino.

Phosphoramidate derivatives have been explored as phosphate prodrugs(e.g., McGuigan et al., J. Med. Chem. 42:393 (1999) and references citedtherein) as shown in Formula G and H.

Cyclic phosphoramidates have also been studied as phosphonate prodrugsbecause of their speculated higher stability compared to non-cyclicphosphoramidates (e.g., Starrett et al., J. Med. Chem. 37:1857 (1994)).

Another type of phosphoramidate prodrug was reported as the combinationof S-acyl-2-thioethyl ester and phosphoramidate (Egron et al.,Nucleosides Nucleotides 18:981 (1999)) as shown in Formula J:

Other prodrugs are possible based on literature reports such assubstituted ethyls, for example, bis(trichloroethyl)esters as disclosedby McGuigan, et al., Bioorg Med. Chem. Lett. 3:1207-1210 (1993), and thephenyl and benzyl combined nucleotide esters reported by Meier, C. etal., Bioorg. Med. Chem. Lett. 7:99-104 (1997).

The structure

has a plane of symmetry running through the phosphorus-oxygen doublebond when R⁶═R⁶, V═W, and V and W are either both pointing up or bothpointing down. The same is true of structures where each —NR⁶ isreplaced with —O—.

The term “cyclic phosphonate ester of 1,3-propane diol”, “cyclicphosphonate diester of 1,3-propane diol”, “2 oxo2λ^(5 [)1,3,2]dioxaphosphonane”, “2 oxo[1,3,2]dioxaphosphonane”,“dioxaphosphonane” refers to the following:

The phrase “together V and Z are connected via an additional 3-5 atomsto form a cyclic group containing 5-7 atoms, optionally containing 1heteroatom, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy,alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom thatis three atoms from both Y groups attached to the phosphorus” includesthe following:

The structure shown above (left) has an additional 3 carbon atoms thatforms a five member cyclic group. Such cyclic groups must possess thelisted substitution to be oxidized.

The phrase “together V and Z are connected via an additional 3-5 atomsto form a cyclic group, optionally containing one heteroatom, that isfused to an aryl group attached at the beta and gamma position to the Yattached to the phosphorus” includes the following:

The phrase “together V and W are connected via an additional 3 carbonatoms to form an optionally substituted cyclic group containing 6 carbonatoms and substituted with one substituent selected from the groupconsisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy,and aryloxycarbonyloxy, attached to one of said additional carbon atomsthat is three atoms from a Y attached to the phosphorus” includes thefollowing:

The structure above has an acyloxy substituent that is three carbonatoms from a Y, and an optional substituent, —CH₃, on the new 6-memberedring. There has to be at least one hydrogen at each of the followingpositions: the carbon attached to Z; both carbons alpha to the carbonlabeled “3”; and the carbon attached to “OC(O)CH₃” above.

The phrase “together W and W′ are connected via an additional 2-5 atomsto form a cyclic group, optionally containing 0-2 heteroatoms, and Vmust be aryl, substituted aryl, heteroaryl, or substituted heteroaryl”includes the following:

The structure above has V=aryl, and a spiro-fused cyclopropyl group forW and W′.

The term “cyclic phosphon(amid)ate” refers to

where Y is independently —O— or —NR^(V)—. The carbon attached to V musthave a C—H bond. The carbon attached to Z must also have a C—H bond.

The naming of the compounds is done by having the ring bearing thegroups R⁵ and R³ be a substituent on the ring bearing the R¹ and R²groups. The naming of the prodrugs is done by having the diaryl systemwith its linker T (Formula I, II, III, V, VI, and VIII) or D (FormulaIV) be a substituent on the phosphorus atom contained in X. For example:[3-R¹-5-R²-4-(4′-R⁵-3′-R³-benzyl)phenoxy]methylphosphonic acidrepresents the formula:

[3-R¹-5-R²-4-(4′-R⁵-3′-R³-phenoxy)phenoxy]methylphosphonic acidrepresents the formula:

N-[3-R¹-5-R²-4-(4′-R⁵-3′-R³-phenoxy)phenyl]carbamoylphosphonic acidrepresents the formula:

2-[(3-R¹-5-R²-4-(4′-R⁵-3′-R³-benzyl)phenoxy)methyl]-4-aryl-2-oxo-2λ⁵-[1,3,2]-dioxaphosphonane:

2-[(3-R¹-5-R²-4-(4′-R⁵-3′-R³-phenoxy)phenoxy)methyl]-4-aryl-2-oxo-2λ⁵-[1,3,2]-dioxaphosphonane:

The term “cis” stereochemistry refers to the spatial relationship of theV group and the carbon attached to the phosphorus atom on thesix-membered ring. The formula below shows a cis stereochemistry.

The term “trans” stereochemistry refers to the spatial relationship ofthe V group and the carbon, attached to the phosphorus atom, on thesix-membered ring. The formula below shows a trans-stereochemistry.

The formula below shows another trans-stereochemistry.

The terms “S-configuration,” “S-isomer” and “S-prodrug” refers to theabsolute configuration S of carbon C′. The formula below shows theS-stereochemistry.

The terms “R-configuration,” “R-isomer” and “R-prodrug” refers to theabsolute configuration R of carbon C′. The formula below shows theR-stereochemistry.

The term “percent enantiomeric excess (% ce)” refers to optical purity.It is obtained by using the following formula:

${\frac{\lbrack R\rbrack - {\lbrack S\rbrack \lbrack R\rbrack} - \lbrack S\rbrack}{\lbrack R\rbrack + \lbrack S\rbrack} \times 100} = {{\% \mspace{14mu} R} - {\% \mspace{14mu} S}}$

where [R] is the amount of the R isomer and [S] is the amount of the Sisomer. This formula provides the % ee when R is the dominant isomer.

The term “enantioenriched” or “enantiomerically enriched” refers to asample of a chiral compound that consists of more of one enantiomer thanthe other. The extent to which a sample is enantiomerically enriched isquantitated by the enantiomeric ratio or the enantiomeric excess.

The term “liver” refers to liver organ.

The term “enhancing” refers to increasing or improving a specificproperty.

The term “liver specificity” refers to the ratio:

$\frac{\left\lbrack {{drug}\mspace{14mu} {or}\mspace{14mu} a\mspace{14mu} {drug}\mspace{14mu} {metabolite}\mspace{14mu} {in}\mspace{14mu} {liver}\mspace{14mu} {tissue}} \right\rbrack}{\left\lbrack {{drug}\mspace{14mu} {or}\mspace{20mu} a\mspace{14mu} {drug}\mspace{14mu} {metabolite}\mspace{14mu} {in}\mspace{14mu} {blood}\mspace{14mu} {or}\mspace{14mu} {another}\mspace{14mu} {tissue}} \right\rbrack}$

as measured in animals treated with the drug or a prodrug. The ratio canbe determined by measuring tissue levels at a specific time or mayrepresent an AUC based on values measured at three or more time points.

The term “phosphorus-containing compounds” refers to compounds thatcontain PO₃H₂, PO₃ ²⁻, PO₂HR, PO₂R⁻, and monoesters and phosphamic acidderivatives thereof.

The term “surrogates of carboxylic acid” refers to groups that possessnear equal molecular shapes and volumes as carboxylic acid and whichexhibit similar physical and biological properties. Examples ofsurrogates of carboxylic acid include, but are not limited to,tetrazole, 6-azauracil, acylsulphonamides, sulfonic acids,thiazolidinedione, hydroxamic acid, oxamic acid, malonamic acid, andcarboxylic acid amides. Because phosphorus-containing thyromimetics(e.g., phosphonic acid-, phosphonic acid monoester-, and phosphinicacid-containing compounds) have a markedly different biological activityas compared to carboxylic acid-containing thyromimetics, phosphonicacid, phosphonic acid monoester, and phosphinic acid are not consideredto be surrogates of carboxylic acid in these compounds.

The term “inhibitor of fructose-1,6-biphosphatase” or “FBPase inhibitor”refers to compounds that inhibit FBPase enzyme activity and therebyblock the conversion of fructose 1,6-bisphosphate, the substrate of theenzyme, to fructose 6-phosphate. These compounds have an IC₅₀ of equalto or less than 50 μM on human liver FBPase measured according to theprocedure found in U.S. Pat. No. 6,489,476.

The term “increased or enhanced liver specificity” refers to an increasein the liver specificity ratio in animals treated with a compound of thepresent invention and a control compound. In one embodiment the testcompound is a phosphorus-containing compound and in another embodimentthe test compound is a prodrug thereof. In one embodiment the controlcompound is a phosphorus-containing compound of the present invention.In another embodiment the control compound is the correspondingcarboxylic acid derivative of the phosphorus-containing test compound.

The term “enhanced oral bioavailability” refers to an increase of atleast 50% of the absorption of the dose of the parent drug, unlessotherwise specified. In an additional aspect the increase in oralbioavailability of the prodrug (compared to the parent drug) is at least100%, that is a doubling of the absorption. Measurement of oralbioavailability usually refers to measurements of the prodrug, drug, ordrug metabolite in blood, plasma, tissues, or urine following oraladministration compared to measurements following systemicadministration of the compound administered orally.

The terms “treating” or “treatment” of a disease includes a slowing ofthe progress or development of a disease after onset or actuallyreversing some or all of the disease effects. Treatment also includespalliative treatment.

The term “preventing” includes a slowing of the progress or developmentof a disease before onset or precluding onset of a disease.

The term “thyroid hormone receptors” (TR) refers to intracellularproteins located in cell nuclei that, following the binding of thyroidhormone, stimulate transcription of specific genes by binding to DNAsequences called thyroid hormone response elements (TREs). In thismanner TR regulates the expression of a wide variety of genes involvedin metabolic processes (e.g., cholesterol homeostasis and fatty acidoxidation) and growth and development in many tissues, including liver,muscle and heart. There are at least two forms of TR; TR alpha (onchromosome 17) and TR beta (on chromosome 3). Each of these isoformsalso has two main isoforms: TR alpha-1 and TR alpha-2; and TR beta-1 andTR beta-2, respectively. TRs are high affinity receptors for thyroidhormones, especially triiodothyronine.

The term “ACC” refers to acetyl CoA carboxylase.

The term “FAS” refers to fatty acid synthase.

The term “spot-14” refers to a 17 kilodalton protein expressed inlipogenic tissues and is postulated to play a role in thyroid hormonestimulation of lipogenesis. (Campbell, M C et al., Endocrinology 10:1210(2003).

The term “CPT-1” refers to carnitine palmitoyltransferase-1.

The term “CYP7A” refers to cholesterol 7-alpha hydroxylase, which is amembrane-bound cytochrome P450 enzyme that catalyzes the7-alpha-hydroxylation of cholesterol in the presence of molecular oxygenand NADPH-ferrihemoprotein reductase. CYP7A, encoded by CYP7, convertscholesterol to 7-alpha-hydroxycholesterol which is the first andrate-limiting step in the synthesis of bile acids.

The term “apoAI” refers to Apolipoprotein AI found in HDL andchylomicrons. It is an activator of LCAT and a ligand for the HDLreceptor.

The term “mGPDH” refers to mitochondrial glycerol-3-phosphatedehydrogenase.

The term “hypercholesterolemia” refers to presence of an abnormallylarge amount of cholesterol in the cells and plasma of the circulatingblood.

The term “hyperlipidemia” or “lipemia” refers to the presence of anabnormally large amount of lipids in the circulating blood.

The term “atherosclerosis” refers to a condition characterized byirregularly distributed lipid deposits in the intima of large andmedium-sized arteries wherein such deposits provoke fibrosis andcalcification. Atherosclerosis raises the risk of angina, stroke, heartattack, or other cardiac or cardiovascular conditions.

The term “obesity” refers to the condition of being obese. Being obeseis defined as a body mass index (BMMD of 30.0 or greater; and extremeobesity is defined at a BMI of 40 or greater. “Overweight” is defined asa body mass index of 25.0 to 29.9 (This is generally about 10 percentover an ideal body weight)

The term “coronary heart disease” or “coronary disease” refers to animbalance between myocardial functional requirements and the capacity ofthe coronary vessels to supply sufficient blood flow. It is a form ofmyocardial ischemia (insufficient blood supply to the heart muscle)caused by a decreased capacity of the coronary vessels.

The term “diabetes” refers to a heterogeneous group of disorders thatshare glucose intolerance in common. It refers to disorders in whichcarbohydrate utilization is reduced and that of lipid and proteinenhanced; and may be characterized by hyperglycemia, glycosuria,ketoacidosis, neuropathy, or nephropathy.

The term “non-insulin-dependent diabetes mellitus” (NIDDM or type 2diabetes) refers to a heterogeneous disorder characterized by impairedinsulin secretion by the pancreas and insulin resistance in tissues suchas the liver, muscle and adipose tissue. The manifestations of thedisease include one or more of the following: impaired glucosetolerance, fasting hyperglycemia, glycosuria, increased hepatic glucoseoutput, reduced hepatic glucose uptake and glycogen storage, reducedwhole body glucose uptake and utilization, dyslipidemia, fatty liver,ketoacidosis, microvascular diseases such as retinopathy, nephropathyand neuropathy, and macrovascular diseases such as coronary heartdisease.

The term “impaired glucose tolerance (IGT)” refers to a condition knownto precede the development of overt type 2 diabetes. It is characterizedby abnormal blood glucose excursions following a meal. The currentcriteria for the diagnosis of IGT are based on 2-h plasma glucose levelspost a 75g oral glucose test (144-199 mg/dL). Although variable frompopulation to population studied, IGT progresses to full blown NIDDM ata rate of 1.5 to 7.3% per year, with a mean of 3-4% per year.Individuals with IGT are believed to have a 6 to 10-fold increased riskin developing NIDDM. IGT is an independent risk factor for thedevelopment of cardiovascular disease.

The terms “fatty liver” and “liver steatosis” are interchangeable andrefer to a disease or disorder characterized by significant lipiddeposition in the liver hepatocytes (parenchyma cells). Simple fattyliver or liver steatosis is not associated with any other liverabnormalities such as scarring or inflammation. Fatty liver or liversteatosis is a common occurrence in patients who are very overweight orhave diabetes mellitus.

The term “NonAlcoholic SteatoHepatitis (NASH) refers to a disease ordisorder characterized by inflammation of the liver in combination withfatty liver. NASH is a possible diagnosis when other causes of liverinflammation such as hepatitis B and C viruses, autoimmune disorders,alcohol, drug toxicity, and the accumulation of copper (Wilson'sDisease) or iron (hemochromatosis) are excluded.

The term “NonAlcoholic Fatty Liver Disease (NAFLD) refers to a widespectrum of liver disease ranging from (and including) simple fattyliver (steatosis), to nonalcoholic steatohepatitis (NASH), to cirrhosis(advanced scarring of the liver). All of the stages of NAFLD have fattyliver in common. In NASH, fat accumulation is associated with varyingdegrees of inflammation (hepatitis) which may lead to scarring(fibrosis) of the liver.

Steatosis can be most readily diagnosed with noninvasive imagingmodalities, such as ultrasound, magnetic resonance imaging, or computedtomography as examples, or following a percutaneous biopsy. Usingultrasound as an example of a noninvasive imaging diagnosis tool, thesonographic findings of diffuse fatty change include a diffusehyperechoic echotexture (bright liver), increased liver echotexturecompared with the kidneys, vascular blurring, and deep attenuation(Yajima et al., Tohoku J Exp Med 139(1):43-50 (1983)). Usingpercutaneous biopsy, the histological features of NAFLD areindistinguishable from those of alcohol-induced liver disease, of which,predominant macrovesicular steatosis alone in >33% of hepatocytes willbe used as the definition. Other histologic features, such as varyingamounts of cytologic ballooning and spotty necrosis, scattered mixedneutrophilic-lymphocytic inflammation, glycogen nuclei, Mallory'shyaline, and perisinusoidal fibrosis may be present, but are notrequired for a diagnosis of NAFLD.

The term “insulin resistance” is defined clinically as the impairedability of a known quantity of exogenous or endogenous insulin toincrease whole body glucose uptake and utilization. As insulin regulatesa wide variety of metabolic processes in addition to glucose homeostasis(e.g., lipid and protein metabolism), the manifestations of insulinresistance are diverse and include one or more of the following: glucoseintolerance, hyperinsulinemia, a characteristic dyslipidemia (hightriglycerides; low high-density lipoprotein cholesterol, and small,dense low-density lipoprotein cholesterol), obesity, upper-body fatdistribution, fat accumulation in the liver (non-alcoholic fatty liverdisease), NASH (non-alcoholic steatohepatitis), increased hepaticglucose output, reduced hepatic glucose uptake and storage intoglycogen, hypertension, and increased prothrombotic and antifibrinolyticfactors. This cluster of cardiovascular-metabolic abnormalities iscommonly referred to as “The Insulin Resistance Syndrome” or “TheMetabolic Syndrome” and may lead to the development of type 2 diabetes,accelerated atherosclerosis, hypertension or polycystic ovariansyndrome.

The Metabolic Syndrome” or “Metabolic Syndrome X” is characterized by agroup of metabolic risk factors in one person. They include:

-   -   Central obesity (excessive fat tissue in and around the abdomen)    -   Atherogenic dyslipidemia (blood fat disorders—mainly high        triglycerides and low HDL cholesterol—that foster plaque        buildups in artery walls)    -   Raised blood pressure (130/85 mmHg or higher)    -   Insulin resistance or glucose intolerance (the body can't        properly use insulin or blood sugar)    -   Prothrombotic state (e.g., high fibrinogen or plasminogen        activator inhibitor [−1] in the blood)    -   Proinflammatory state (e.g., elevated high-sensitivity        C-reactive protein in the blood)

According to the present invention, “Metabolic Syndrome” or “MetabolicSyndrome X” is identified by the presence of three or more of thesecomponents:

-   -   Central obesity as measured by waist circumference:        -   Men: Greater than 40 inches        -   Women: Greater than 35 inches    -   Fasting blood triglycerides greater than or equal to 150 mg/dL    -   Blood HDL cholesterol:    -   Men: Less than 40 mg/dL    -   Women: Less than 50 mg/dL    -   Blood pressure greater than or equal to 130/85 mmHg    -   Fasting glucose greater than or equal to 110 mg/dL

The term “thyroid responsive element” or “TRE” refers to an element thatusually consists of directly repeated half-sites with the consensussequence AGGTCA. (Harbers et al., Nucleic Acids Res. 24(12):2252-2259(1996)). TREs contain two half-sites of the AGGTCA motif which can bearranged as direct repeats, inverted repeats, or everted repeats.

The term “thyroid responsive genes” refers to genes whose expression isaffected by triiodothyronine (Menjo et al., Thyroid 9(9):959-67 (1999);Helbing et al., Mol. Endocrinol. 17(7):1395-409 (2003)).

The term “TSH” or “thyrotropin” refers to thyroid stimulating hormone.

The term “atherogenic proteins” refers to proteins that induce,stimulate, enhance or prolong atherosclerosis and diseases related toatherosclerosis, including but not limited to coronary heart disease.Atherogenic proteins include apoAI and Lp (a).

The term “thyroid hormone, or TH” includes for example natural iodinatedthyronines from thyroglobulin (e.g., T3, T4), as well as drugs such asLevothyroxine sodium which is the sodium salt of a levorotatory isomerof T4 and a commonly used drug as replacement therapy in hypothyroidism.Other uses include the treatment of simple nonendemic goiter, chroniclymphocytic thyroiditis and thyrotropin-dependent thyroid carcinoma.Liothyronine sodium is the sodium salt of a levorotatory isomer of T3.Liotrix is a 4:1 mixture of levothyroxine and liothronine. Thyroid is apreparation derived from dried and defatted thyroid glands of animals.

The term “thyromimetic” or “T3 mimetic” as used herein, is intended tocover any moiety which binds to a thyroid receptor and acts as anagonist, antagonist, partial agonist/antagonist, or inverse agonist ofT3. The thyromimetic may be further specified as an agonist, anantagonist, a partial agonist, or a partial antagonist. Thethyromimetics of the present invention presumably bind the T3 bindingsite and can inhibit T3 binding to a thyroid hormone receptor utilizinga heterologous displacement reaction. Thyromimetics of the presentinvention that can produce one of or more of the effects mediated bynaturally occurring T3 in a target tissue or cell would be considered anagonist or partial agonist. Thyromimetics of the present invention thatcan inhibit one of more of the effects mediated by naturally occurringT3 in a target tissue or cell would be considered an antagonist, partialagonist, or inverse agonist. Thyromimetics do not include T3, T4, orother naturally occurring thyroid hormones.

The term “metabolic disease” includes diseases and conditions such asobesity, diabetes and lipid disorders such as hypercholesterolemia,hyperlipidemia, hypertriglyceridemia as well as disorders that areassociated with abnormal levels of lipoproteins, lipids, carbohydratesand insulin such as metabolic syndrome X, diabetes, impaired glucosetolerance, atherosclerosis, coronary heart disease, cardiovasculardisease.

The term “mitochondrial biogenesis” or “mitochondrialgenesis” refers tothe rate at which nascent mitochondria are synthesized. Mitochondrialbiogenesis that occurs during cell replication provides enough newmitochondria for both the parent and daughter cells. Mitochondrialbiogenesis that occurs in the absence of cell replication leads to anincrease in the number of mitochondria within a cell.

As used herein, the term “significant” or “statistically significant”means a result (i.e. experimental assay result) where the p-value is≦0.05 (i.e. the chance of a type I error is less than 5%) as determinedby an art-accepted measure of statistical significance appropriate tothe experimental design.

All references cited herein are incorporated by reference in theirentirety.

DETAILED DESCRIPTION

The present invention relates to methods of decreasing the fat contentof the liver in an animal comprising administering thyromimeticcompounds, pharmaceutically acceptable salts and prodrugs thereof, andpharmaceutically acceptable salts of the prodrugs, where the compoundsbind to a thyroid hormone receptor.

The present invention further relates to methods of preventing,treating, or ameliorating fatty liver diseases in an animal comprisingadministering thyromimetic compounds, pharmaceutically acceptable saltsand prodrugs thereof, and pharmaceutically acceptable salts of theprodrugs, where the compounds bind to a thyroid hormone receptor.

Thyroid hormones and thyroid hormone mimetics bind to thyroid hormonereceptors in the nucleus of cells and can change expression levels ofgenes encoding proteins that play an important role in metabolicdiseases. By altering the expression of thyroid hormone-responsive genesin the liver, thyromimetic compounds can decrease the level of fat inthe liver. Fatty liver diseases that can be prevented, treated, orameliorated with thyroid hormone mimetics include steatosis,non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis(NASH).

In one aspect, the thyromimetic compounds, pharmaceutically acceptablesalts and prodrugs thereof, and pharmaceutically acceptable salts of theprodrugs used in these methods bind to at least one thyroid hormonereceptor with an Ki of ≦100 nM relative to T3, or ≦90 nM, ≦80 nM, ≦70nM, ≦60 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦10 nM, ≦50 nM, ≦1 nM, ≦0.5nM. Thyroid hormone receptor binding is readily determined using assaysdescribed in the literature. For example, nuclear extracts from animallivers can be prepared according to the methods described by Yokoyama etal. (J. Med. Chem., 38: 695-707 (1995)). Binding assays can also beperformed using purified thyroid hormone receptors. For example, usingthe methods used by Chiellini et al. (Bioorg. Med. Chem., 10: 333-346(2002)) competition ligand binding affinities are determined using¹²⁵I-T3 and the human thyroid receptors TRα1 and TRβ1. The lattermethods advantageously enable determination of thyroid receptorselectivity.

In another aspect, the thyromimetic compounds, pharmaceuticallyacceptable salts and prodrugs thereof, and pharmaceutically acceptablesalts of the prodrugs used in these methods cause at least a 50%, 2fold, 3 fold, 4 fold, 6 fold or 8 fold increase or decrease in theexpression of one or more thyroid hormone-responsive genes. Changes ingene expression can be detected in cells or in vivo. Prodrugs of thethyromimetics can increase cellular uptake but in some cases are poorlyconverted to the active compound due to low levels of the enzymesrequired for the conversion. Changes in gene expression in vivo requireeither the compounds of the invention to be taken up by the tissuefollowing administration or for the prodrug to remain intact afteradministration long enough to distribute to the target organ and cell.Following distribution to the cell, enzymes or other conditionsresponsible for cleaving the prodrug must act on the prodrug and convertit to the active compound. The compound must then be able to betransported to the nucleus. If a portion of the compound is excretedfrom the cell it must be retransported back across the cellular membraneand nuclear membrane. The prodrugs of the present invention that areactivated in the liver and excreted by the liver as active compounds areretransported back across the cellular and nuclear membrane and into thenucleus.

The liver is a major target organ of thyroid hormone with an estimated8% of the hepatic genes regulated by thyroid hormone. Quantitativefluorescent-labeled cDNA microarray hybridization was used to identifythyroid-responsive genes in the liver as shown in Table 1 below (Feng etal., Mol. Endocrinol., 14: 947-955 (2000)). Hepatic RNA from T3-treatedand hypothyroid mice were used in the study. Thyroid hormone treatmentaffected the expression of 55 genes from the 2225 different mouse genessampled with 14 increasing >2-fold and 41 decreasing >60%.

TABLE 1 GENES REGULATED BY T3 List of Hepatic Genes Regulated by T3Determined by cDNA Microarray Analyses Function Accession Clone ID GenesNo. Fold Carbohydrate and fatty acid metabolism, and insulin action580906 Spot 14 gene X95279 8.8 523120 Glucose-6-phosphatase U00445 3.8615159 Carbonyl reductase (Cbr1) U31966 3.3 571409 Insulin-like growthfactor binding protein 1 precursor X81579 3.0 481636 Fatty acidtransport protein (FATP) U15976 1.8 550993 Cyp4a-10 X69296 0.3 583329PHAS-II U75530 0.3 616283 Serine/threonine kinase (Akt2) U22445 0.3583333 Putative transcription factor of the insulin gene X17500 0.3533177 Nuclear-encoded mitochondrial acyltransferase L42996 0.2 608607Glycerophosphate dehydrogenase J02655 0.3 Cell proliferation,Replication 614275 B61 U26188 2.3 597868 Bcl-3 M90397 2.5 493127Kinesin-like protein (Kip1p) AF131865 2.0 582689Chromodomain-helicase-DNA binding protein CHD-1 P40201 0.4 524471NfiB1-protein (exon 1-12) Y07685 0.3 516208 Putative ATP-dependent RNAhelicase PL10 J04847 0.3 558121 Murine vik5variant in the kinase S532160.1 573247 C11 protein X81624 0.3 522108 Thymic stromal stimulatingfactor D43804 0.3 613942 Ubiquitin-activating enzyme E1 X D10576 0.3Signal transduction 573046 β-2 Adrenergic receptor X15643 3.4 583258Protein kinase C inhibitor (mPKCl) U60001 2.1 616040 Inhibitory Gprotein of adenylate cyclase, α chain M13963 0.3 583353 Terminaldeoxynucleotidyltransferase 04123 0.3 550956 Rho-associated, coiled-coilforming protein kinase p160 U58513 0.2 582973 Protein kinase C, Θ typeAB011812 0.3 442989 Protein kinase ζ M94632 0.5 607870 Lamin A D131810.3 Glycoprotein synthesis 375144 α-2,3-Sialyltransferase D28941 0.3481883 β-Galactoside α 2,6-sialyltransferase D16106 0.3 Cellularimmunity 615872 T-complex protein 1, d subunit P80315 0.3 618426 H-2class I histocompatibility antigen Q61147 0.3 614012 FK506-bindingprotein (FKBP65) L07063 0.3 604923 FK506-binding protein (FKBP23)AF040252 0.2 Cytoskeletal protein 374030 Myosin binding protein H(MyBP-H) U68267 2.2 613905 AM2 receptor X67469 0.3 616518 Cytoskeletalβ-actin X03672 0.3 614948 Actin, α cardiac M15501 0.3 607364 Skeletalmuscle actin M12866 0.3 597566 Capping protein a-subunit G565961 0.3483226 Actin, γ-enteric smooth muscle M26689 0.3 Others 552837 Majorurinary protein 2 precursor M27608 3.9 521118 β-Globin AB020013 2.3493218 α-Globin L75940 2.7 585883 Putative SH3-containing protein SH3P12AF078667 0.3 615239 Membrane-type matrix metalloproteinase X83536 0.2402408 ece1 (endothelin-converting enzyme) W78610 0.2 635768 α-AdaptinP17426 0.3 634827 Glucose regulated protein 78 D78645 0.3 616189 Lupusla protein homolog L00993 0.3 588337 EST AI646753 0.4 335579 Virus-like(VL30) retrotransposon BVL-1 X17124 0.3 557037 TGN38B D50032 0.3 597390Mitochondrial genome L07096 0.4 616563 Arylsulfatase A X73230 0.3

Genes reported to be affected by thyroid hormone are identified using avariety of techniques include microarray analysis. Studies haveidentified genes that are affected by T3 and T3 mimetics that areimportant in metabolic diseases.

T3-responsive genes in the liver include genes affecting lipogenesis,including spot 14, fatty acid transport protein, malic enzyme, fattyacid synthase (Blennemann et al., Mol. Cell. Endocrinol. 110(1-2):1-8(1995)) and CYP4A. HMG CoA reductase and LDL receptor genes have beenidentified as affecting cholesterol synthesis and as being responsive toT3. CPT-1 is a T3 responsive gene involved in fatty acid oxidation.Genes affecting energy expenditure, including mitochondrial genes suchas mitochondrial sn-glycerol 3-phosphate dehydrogenase (mGPDH), and/orenzymes associated with proton leakage such as the adenine nucleotidetransporter (ANT), Na⁺/K⁺-ATPase, Ca²⁺-ATPase and ATP synthase are alsoT3 responsive genes. T3 responsive genes affecting glycogenolysis andgluconeogenesis, include glucose 6-phosphatase and PEPCK.

Compounds used in the methods bind to thyroid receptors and produce achange in some hepatic gene expression. Evidence for agonist activity isobtained using standard assays described in the literature. One assaycommonly used entails a reporter cell assay wherein cells, e.g., HeLacells, Hek293 cells, Chinese hamster ovary cells, are transfected withan expression vector for human TRα1 or TRβ1 and subsequently with areporter vector encoding a secreted form of alkaline phosphatasecontaining whose expression is under the control of a thyroid hormoneresponse element. Agonist activity is measured by exposing the cells tothe compounds, especially prodrugs of the compounds that are cleaved tothe active compound by cell homogenates, followed by determiningalkaline phosphatase activity in the cell culture medium using achemiluminescent assay (Grover et al., Proc. Natl. Acad. Sci. U.S.A.,100(17):10067-72 (2003)).

Particularly useful T3 mimetics in these methods would minimize effectson thyroid function, thyroid production of circulating iodinatedthyronines such as T3 and T4, and/or the ratio of T3 to T4. Some T3mimetics distribute more readily to the liver and result inpharmacological effects at doses that do not adversely affect thyroidfunction, thyroid production of circulating iodinated thyronines such asT3 and T4, and/or the ratio of T3 to T4. In one embodiment the compoundsused in the present invention have a therapeutic index, defined as thedifference between the dose at which a significant effect is observedfor a use disclosed herein, e.g., decreasing fat content in the liver,and the dose at which a significant decrease in T3 or significantdecrease in T4, or significant change in the ratio of T3 to T4 isobserved, is at least 50 fold, 100 fold, 200 fold, 300 fold, 400 fold,500 fold, 600 fold, 700 fold, 800 fold, 900 fold, 1000 fold, 2000 fold,3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000fold or at least 10000 fold. In one embodiment, rather than asignificant amount, the amount of change in T3 or T4 is a decreaseselected from; at least 5%, 10%, 15%, 20%, 25% or at least 30% ofcirculating levels.

As discussed above, the previous use of T3 and T3 mimetics to treatmetabolic diseases have been limited by the deleterious side-effects onthe heart. Attempts to overcome this limitation have focused onselectively targeting the liver over the heart using T3 mimetics thatselectively bind TRβ, over TRα. Because the heart expresses mainly TRα,previous investigators have attempted to increase the therapeutic indexof T3 mimetics by increasing the selectively of the compounds for TRβwhich is expressed in the liver. Other work has led to the discovery ofphosphorus-containing compounds, including prodrugs, that selectivelydistribute to the liver over the heart. These compounds are able toselectively target the liver and thereby increase the therapeutic indexas compared to T3 and T3 mimetics containing a carboxylic acid.Compounds having increased liver selectivity, e.g., due toliver-selective distribution or TR selectivity, can therefore be dosedat levels that are effective in treating metabolic and other disorderswhere the liver is the drug target without significantly negativelyaffecting heart function.

Changes in the therapeutic index are readily determined using assays andmethods well described in the literature. Genes in extrahepatic tissuesare monitored using methods well understood by those skilled in the art.Assays include using cDNA microarray analysis of tissues isolated fromtreated animals. The sensitivity of the heart to T3 makes analysis ofT3-responsive genes in the heart as well as the functional consequencesof these changes on cardiac properties one further strategy forevaluating the therapeutic index of the compounds of the presentinvention. Cardiac genes measured include mGPDH, myosin heavy and lightchain. One method of measuring the effects of T3 mimetics on the heartis by the use of assays that measure T3 mediated myosin heavy chain genetranscription in the heart.

A variety of methods are described that provide a means for evaluatingthe functional consequences of T3-cardiac action, including measurementof cardiac hypertrophy (heart weight to body weight ratio), heart rate,and various hemodynamic parameters, including systolic and diastolicarterial pressure, end-systolic left ventricular pressure and maximalspeeds of contraction and relaxation using methods described by Trost etal., (Endocrinology 141:3057-64 (2000)).

Other methods are also available to assess the therapeutic indexincluding effects on muscle wasting and bone density.

The therapeutic index is determined by administering to animals a widerange of doses and determining the minimal dose capable of inducing aresponse in the liver relative to the dose capable of inducing aresponse in the heart.

Some thyromimetic compounds are often poorly transported into culturedcells. Accordingly, cell reporter assays, while often useful forconfirming agonist activity, may not provide a suitable indication ofpotency. Thus, evidence of agonist activity is often more readilyobtained in vivo. In vivo assays include but are not limited to treatinganimals with a thyromimetic or a prodrug and monitoring the expressionof T3-responsive genes in the liver or the functional consequences ofchanges of T3-responsive genes.

In one aspect, compounds useful in the methods of the invention bind tothyroid receptors and produce changes in the expression of two or morehepatic genes. Animals used for testing compounds useful in the methodsinclude normal rats and mice, animals made hypothyroid using methodswell described in the literature, including thyroid hormone receptorknockout mice (e.g., TRα^(−/−) such as those used in Grover et al.,2003), or animals exhibiting high cholesterol (e.g., high cholesterolfed rat or hamster), obesity and/or diabetes (e.g., fa/fa rat, Zuckerdiabetic fatty rat, ob/ob mice, db/db mice, high fat fed rodent).(Liureau et al., Biochem Pharmacol. 35(10):1691-6 (1986); Trost et al.,Endocrinology 141(9):3057-64 (2000); and Grover, PNAS 2003). The drug orprodrug is administered by a variety of routes including by bolusinjection, oral, and continuous infusion. Animals are treated for 1-28days and the liver, heart and blood are isolated. Changes in genetranscription relative to vehicle treated animals and T3-treated animalsare determined using northern blot analysis, RNase protection orreverse-transcription and subsequent PCR. While methods are availablefor monitoring changes in thousands of hepatic genes, only a smallnumber need to be monitored to demonstrate the biological effect ofcompounds in this invention. Typically, genes such as spot-14, FAS,mGPDH, CPT-1, and LDL receptor are monitored. Changes of >1.5 fold intwo or more genes is considered proof that the compound modulatesT3-responsive genes in vivo. Alternative methods for measuring changesin gene transcription include monitoring the activity or expressionlevel of the protein encoded by the gene. For instance, in cases wherethe genes encode enzyme activities (e.g., FAS, mGPDH), directmeasurements of enzyme activity in appropriately extracted liver tissuecan be made using standard enzymological techniques. In cases where thegenes encode receptor functions (e.g., the LDL receptor) ligand bindingstudies or antibody-based assays (e.g., Western blots) can be performedto quantify the number of receptors expressed. Depending on the gene, TRagonists will either increase or decrease enzyme activity or increase ordecrease receptor binding or number.

The functional consequences of changing the expression levels of hepaticgenes responsive to T3 is many-fold and readily demonstrated usingassays well described in the literature. Administering thyromimeticcompounds that bind to a TR to animals can result in changes in lipids,including hepatic and/or plasma cholesterol levels; changes inlipoprotein levels including LDL-cholesterol, lipoprotein a (Lp(a));changes in hepatic glycogen levels; and changes in energy expenditure asmeasured by changes in oxygen consumption and in some cases animalweight. For example, the effect on cholesterol is determined usingcholesterol fed animals such as normal rats and hamsters, or TRα^(−/−)knockout mice. Cholesterol is measured using standard tests. Hepaticglycogen levels are determined from livers isolated from treatedanimals. Changes in energy expenditure are monitored by measuringchanges in oxygen consumption (MV_(O) ₂ ). A variety of methods are welldescribed in the literature and include measurement in the whole animalusing Oxymax chambers (U.S. Pat. No. 6,441,015). Livers from treatedrats can also be evaluated (Fernandez et al., Toxicol Lett. 69(2):205-10(1993)) as well as isolated mitochondria from liver (Carreras et al.,Am. J. Physiol. Heart Circ. Physiol. 281(6):H2282-8 (2001)). Hepatocytesfrom treated rats can also be evaluated (Ismail-Beigi et al., J. Gen.Physiol. 73(3):369-83 (1979)).

Provided are methods of reducing fat content in the liver or ofpreventing, treating, or ameliorating fatty liver disease (e.g.,steatosis, NASH or NAFLD) in an animal, the method comprising the stepof administering to a patient an amount of a thyromimetic compound, aprodrug thereof, or a pharmaceutically acceptable salt or co-crystalthereof. In one embodiment said compound is an active form. In anotherembodiment said compound is a prodrug. In another embodiment saidcompound or a prodrug thereof comprises a stereocenter. In anotherembodiment said compound is administered as a racemic mixture. Inanother embodiment said compound is administered as an enantiomericallyenriched mixture. In another embodiment said compound is administered asa diastereomeric mixture. In still another embodiment said compound isadministered as an individual stereoisomer.

While T3 administration may have some effect on fat content in liver,such effect would only occur at high doses of T3, i.e., doses at whichT3-related toxicities occur. Further, even if T3 administration lowersfat content in liver, the activity decreases over time, e.g., in thespace of four to five weeks. Thus, in one embodiment of the invention,thyromimetic compounds are administered at doses that significantlyreduce fat content in the liver but are below the doses at which aneffect is observed with T3. In an additional embodiment, thyromimeticcompounds are administered that maintain fat-reducing activity for longperiods of time, e.g., 1, 2, 3, 4, 6, 8, 12 weeks or longer without anyloss in efficacy. In a further embodiment, thyromimetic compounds areadministered that maintain fat-reducing activity for long periods oftime, e.g., 1, 2, 3, 4, 6, 8, 12 weeks or longer, wherein efficacy ofthe compounds decreases over time but at a slower rate than the decreasein efficacy observed with T3. For example, the decrease in efficacy maybe about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, or 400% or moreslower than the decrease in efficacy observed with T3.

In another embodiment of the invention, the thyromimetic compoundsreduce fat content in liver without significantly affecting peripheralfat, visceral fat, or epididymal fat. In one embodiment, thethyromimetic compounds reduce fat content in the liver at a faster ratethan the decrease in fat content in other tissues or areas of the body,e.g., skin, abdomen, heart, vasculature, epididymis. In anotherembodiment, the thyromimetic compounds cause an increase in oxidation offree fatty acids in the liver. In a further embodiment, the thyromimeticcompounds increase oxidation of triglycerides, cholesterol esters,and/or long chain acetyl-CoA esters in the liver. In certainembodiments, oxidation is increased by about 10, 20, 30, 40, 50, 60, 70,80, 90, 100, 200, or 400% or more.

In one aspect of the invention, the thyromimetic compounds reduce fatcontent in liver in the absence of any negative effects on the heart.Negative effects include one or more of significant increase in heartrate, significant raising of blood pressure, significant increase inheart rate, significant increase in left ventricular contractility,significant increase in systolic blood pressure, and significantincrease in diastolic blood pressure.

In another aspect of the invention, the thyromimetic compounds reducefat content in liver in the absence of any significant change in totalbody weight, significant change in TSH or TRH levels, significant changein liver enzymes, significant change in serum free fatty acid levels, orsignificant liver mitochondrial damage.

Provided are pharmaceutical compositions a compound useful in thepresent invention. Also provided are pharmaceutical compositions of thepresent invention having an oral bioavailability of least 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% 75% or at least 80%.

Also provided are pharmaceutical compositions comprising a firstcompound useful in the present invention and a second compound usefulfor decreasing the fat content of the liver, useful for the prevention,treatment, or amelioration of a fatty liver disease such as steatosis,NASH, or NAFLD, or useful for the prevention, treatment, or ameliorationof a disease or disorder that is related to or results in fatty liverdisease. In one embodiment, a composition comprising said first andsecond compound is a single unit dose. In another embodiment, said unitdoes is in the form of a tablet, hard capsule or soft gel capsule.

Also provided are kits for decreasing that fat content of liver or forthe prevention, treatment, or amelioration of a fatty liver disease suchas steatosis, NASH, or NAFLD, the kits comprising:

a) a first pharmaceutical composition comprising a thyromimetic compoundor a prodrug thereof;

b) a second pharmaceutical composition comprising an additional compounduseful for decreasing the fat content of the liver, useful for theprevention, treatment, or amelioration of a fatty liver disease such assteatosis, NASH, or NAFLD, or useful for the prevention, treatment, oramelioration of a disease or disorder that is related to or results infatty liver disease; and

c) at least one container for containing said first or second or bothfirst and second pharmaceutical composition.

Also provided is the use of a compound of the present invention for themanufacture of a medicament for decreasing the fat content of liver orfor the prevention, treatment or amelioration of a fatty liver diseasesuch as steatosis, NASH, and NAFLD.

In one embodiment, compounds used in the present methods are compoundsthat selectively distribute to the liver. In one embodiment, thecompounds have at least 10 fold, 25 fold, 50 fold, 75 fold, 100 fold,200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold,900 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold 6000fold, 7000 fold, 8000 fold, 9000 fold, 10,000 fold, 20,000 fold, 30,000fold, 40,000 fold or 50,000 fold greater selectivity. In one embodimentthe selectivity for the liver is compared to the heart. In anotherembodiment the selectivity for the liver is compared to the pituitary.In another embodiment the selectivity for the liver is compared to thekidney.

In a further embodiment, compounds used in the present methods arecompounds of the present invention that bind at least one thyroidhormone receptor with an Ki of ≦100 nM, ≦90 nM, ≦80 nM, ≦70 nM, ≦60 nM,≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦10 nM, ≦50 nM, ≦1 nM, or ≦0.5 nMrelative to T3. In one embodiment said thyroid hormone receptor is TRα.In one embodiment said thyroid hormone receptor is TRβ. Also providedare compounds that bind at least one thyroid hormone receptor with an Kiof ≧100 nM, ≧90 nM, ≧80 nM, ≧70 nM, ≧60 nM, ≧50 nM, ≧40 nM, ≧30 nM, ≧20nM, ≧10 nM, ≧50 nM, ≧1 nM, or ≧0.5 nM relative to T3, but in each case≦150 nM. In one embodiment said thyroid hormone receptor is TRα. In oneembodiment said thyroid hormone receptor is TRβ. In one embodiment saidthyroid hormone receptor is TRα1. In one embodiment said thyroid hormonereceptor is TRβ1. In one embodiment said thyroid hormone receptor isTRα2. In one embodiment said thyroid hormone receptor is TRβ2.

Novel methods described herein describe the use of thyromimeticcompounds that bind to TRs. In one aspect, compounds described belowinclude compounds of Formula I-IX. The compounds of the presentinvention can be used in the methods described herein.

Compounds Useful in the Invention

The compounds useful in the invention are thyromimetic compounds thatbind to and activate thyroid receptors in the liver. The presentinvention relates to compounds of Formula I-IX, including stereoisomersand mixtures of stereoisomers thereof, pharmaceutically acceptable saltsthereof, co-crystals thereof, and prodrugs (including stereoisomers andmixtures of stereoisomers thereof) thereof, and pharmaceuticallyacceptable salts and co-crystals of the prodrugs.

The compounds of the present invention may be either crystalline,amorphous or a mixture thereof. Compositions comprising a crystallineform a compound of the present invention may contain only onecrystalline form of said compound or more than one crystalline form. Forexample, the composition may contain two or more different polymorphs.The polymorphs may be two different polymorphs of the free form, two ormore polymorphs of different co-crystal forms, two or more polymorphs ofdifferent salt forms, a combination of one or more polymorphs of one ormore co-crystal forms and one or more polymorphs of the free form, acombination of one or more polymorphs of one or more salt forms and oneor more polymorphs of the free form, or a combination of one or morepolymorphs of one or more co-crystal forms and one or more polymorphs ofone or more salt forms.

Pharmaceutically acceptable base addition salts of the compounds hereinare included in the present invention. Pharmaceutically acceptable baseaddition salts refers to those salts which retain the biologicaleffectiveness and properties of the free acids, which are notbiologically or otherwise undesirable. These salts are prepared fromaddition of an inorganic base or an organic base to the free acid. Saltsderived from inorganic bases include, but are not limited to: sodium,potassium, lithium, ammonium, calcium, magnesium, zinc, aluminum saltsand the like. Preferred inorganic salts are the ammonium, sodium,potassium, calcium, and magnesium salts. Salts derived from organicbases include, but are not limited to, salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine,arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike.

Pharmaceutically acceptable acid addition salts of the compounds hereinhaving a base functional group (e.g., a prodrug whereby the carboxylicacid or surrogate thereof is protected with a group comprising a basefunctional group) are also included in the present invention.Pharmaceutically acceptable acid addition salts refer to those saltswhich retain the biological effectiveness and properties of the freebase, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic acid or an organic acid tothe free base. Salts derived from inorganic acids include, but are notlimited to: acistrate, hydrobromide, hydrochloride, sulfate, bisulfate,nitrate, acetate, oxalate, besylate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, laurylsulphonate. bromide, fumarate, pamoate, glucuronate,hydroiodide, iodide, sulfate, xinofoate and chloride salts.

The compounds of the present invention may be pure or substantially pureor have a purity of at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99% or a purity at least 99.5%. The compounds mayalso be part of a pharmaceutically acceptable composition. The compoundsmay also be part of a biological material or sample. Thus, included inthe present invention are cells and tissues comprising a compound of thepresent invention. The cells or tissues can be in vivo, ex vivo or invitro. Examples include liver or liver cells (e.g., hepatocytes), blood,gastric fluid (simulated or actual), intestinal fluid (simulated oractual) and urine.

In one aspect, the invention relates to the use of a compound of FormulaI:

(Ar¹)-G-(Ar²)-T-E

wherein:

Ar¹ and Ar² are substituted aryl groups;

G is an atom or group of atoms that links Ar¹ and Ar² through a singleC, S, Se, O, or N atom or CH₂ linked to C, S, Se, O, or N, wherein the Cor N is substituted;

T is an atom or group of atoms linking Ar² to E through 1-4 contiguousatoms or is absent; and

E is a functional group or moiety with a pKa≦7.4, carboxylic acid oresters thereof, sulfonic acid, tetrazole, hydroxamic acid, 6-azauracil,thiazolidinedione, acylsulfonamide, other carboxylic acid surrogatesknown in the art, phosphonic acid, phosphonic acid monoester, phosphinicacid, or a prodrug thereof, or an atom or group of atoms containing an Oor N that binds the thyroid hormone binding pocket of a TRα or TRβ.

In another aspect, the invention relates to the use of a compound ofFormula II:

wherein:

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-, orCH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰—R¹¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(n)—CR^(b)═CR^(b)—, (CR^(a)₂)—CR^(b)═CR^(b)—(CR^(a) ₂)_(k)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—, —S(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—,—N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(m)C(R^(b))(NR^(b)R^(c))—,C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b)₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, (CR^(b)₂)—N(R^(c))—(CR^(b) ₂)—(CR^(b) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—O—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a)₂)—;

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹, R², R⁶, and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, optionally substituted —C₁-C₄ alkyl,optionally substituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, hydroxyand cyano; or

R⁶ and T are taken together along with the carbons they are attached toform a ring of 5 to 6 atoms with 0-2 unsaturations, not including theunsaturation on the ring to which R⁶ and T are attached, including 0 to2 heteroatoms independently selected from —NR^(i)—, —O—, and —S—, withthe proviso that when there are 2 heteroatoms in the ring and bothheteroatoms are different than nitrogen then both heteroatoms have to beseparated by at least one carbon atom; and X is attached to this ring bya direct bond to a ring carbon, or by —(CR^(a) ₂)— or —C(O)— bonded to aring carbon or a ring nitrogen;

R^(i) is selected from the group consisting of hydrogen, —C(O)C₁-C₄alkyl and —C₁-C₄ alkyl; or

R¹ and R⁷ are taken together along with the carbons to which they areattached to form an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R¹and R⁷ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted-O—C₁-C₃ alkyl, hydroxy, —(CR^(a)₂)aryl, —(CR2)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl,—C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CB:F₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))-cycloalkyl,—C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),SR^(d), S(═O)R^(c), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g),—C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NeR^(f)R^(g),—N(R^(b))S(═O)₂R^(e), —N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂),aryl, optionally substituted —(CR^(b)₂),cycloalkyl, and optionally substituted —(CR^(b) ₂),heterocycloalkyl,or R^(f) and R^(g) may together form an optionally substitutedheterocyclic ring of 3-8 atoms containing 0-4 unsaturations, saidheterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl; or

R³ and R⁸ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 to 6 atoms with0-2 unsaturations, not including the unsaturation on the ring to whichR³ and R⁸ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, O—, and—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;or

R⁵ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R⁵ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another aspect, the invention relates to the use of a compound ofFormula III:

wherein:

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-, orCH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b)(CR^(a) ₂)_(n), —(CR^(a) ₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a)₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n), —S(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—,N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(m)C(R^(b))(NR^(b)R^(c))—,—C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b)₂)—(CR^(a) ₂)_(p)—, (CR^(b) ₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)—(CR^(b) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—O—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a)₂)—;

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano; withthe proviso that at least one of R¹ and R² is not hydrogen;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))-cycloalkyl,—C(C^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),—SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e),—N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring of 3-8 atoms containing 0-4unsaturations, said heterocyclic ring may contain a second heterogroupwithin the ring selected from the group consisting of O, NR^(c), and S,wherein said optionally substituted heterocyclic ring may be substitutedwith 0-4 substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR²)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or

R³ and R¹ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R⁵ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In one embodiment of the compound of Formula III:

G is selected from the group consisting of —O—, —S, and —CH₂;

T is selected from the group consisting of —(CR^(a) ₂)_(n)—, —O(CR^(b)₂)(CR^(a) ₂)_(p)—, —S(CR^(b) ₂)(CR^(a) ₂)_(p)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(p)—, —N(R^(b))C(O)(CR^(a) ₂)_(p)—, —(CR^(a)₂)CH(NR^(b)R^(c))—, and —C(O)NH(CR^(b) ₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c)C; with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(c) is independently selected from the group consisting ofhydrogen and —CH₃, —C(O)—CH₃, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, —CH₃, —CF₃, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, halogen, andoptionally substituted —C₁-C₆ alkyl;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂),cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring, said heterocyclic ring maycontain a second heterogroup within the ring selected from the groupconsisting of O, NR^(c), and S, wherein said optionally substitutedheterocyclic ring may be substituted with 0-4 substituents selected fromthe group consisting of optionally substituted —C₁-C₄ alkyl, —OR^(b),oxo, cyano, —CF₃, optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R¹ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another embodiment of the compound of Formula III:

G is selected from the group consisting of —O—, —S, and —CH₂;

T is selected from the group consisting of a bond, —(CH₂)_(n)—, —OCH₂—,—SCH₂—, —NHCH₂—, —NHC(O)(CH₂)_(p)—, and —(CH₂)CH(NH₂)—, and—C(O)NH(CH₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

R¹ and R² are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with the proviso that atleast one of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl,optionally substituted —CH(OH)aryl, optionally substituted—(CH₂)cycloalkyl, optionally substituted —CH(OH)cycloalkyl, optionallysubstituted —(CH₂)heterocycloalkyl, optionally substituted—CH(OH)heterocycloalkyl, —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, F, Cl, Br, iodo,and CH₃;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂),cycloalkyl,and optionally substituted —(CH₂),heterocycloalkyl, or R^(f) and R^(g)may together form an optionally substituted heterocyclic ring, saidheterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another aspect, the invention relates to the use of a compound ofFormula IV:

wherein:

A is selected from the group consisting of —NR^(i)—, —O—, and —S—;

B is selected from the group consisting of —CR^(b)—, and —N—;

R^(i) is selected from the group consisting of hydrogen, —C(O)C₁-C₄alkyl and —C₁-C₄ alkyl;

R^(b) is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl;

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

D is selected from the group consisting of a bond, —(CR^(a) ₂)—, and—C(O)—;

n is an integer from 0-2;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

R¹ and R² are each independently selected from the group consisting ofhalogen, optionally substituted —C₁-C₄ alkyl, optionally substituted—S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl, optionallysubstituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F,optionally substituted —O—C₁-C₃ alkyl, and cyano;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))-cycloalkyl,—C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),—SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e),—N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂),cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring of 3-8 atoms containing 0-4unsaturations, which may contain a second heterogroup selected from thegroup consisting of O, NR^(c), and S, wherein said optionallysubstituted heterocyclic ring may be substituted with 0-4 substituentsselected from the group consisting of optionally substituted —C₁-C₄alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F, optionally substitutedphenyl, and —C(O)OR^(b);

Each R^(b) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In one embodiment of the compound of Formula IV:

A is selected from the group consisting of —NR^(i)—, —O—, and —S—,

B is selected from the group consisting of —CR^(b)—, and —N—;

R^(i) is selected from the group consisting of hydrogen, —C(O)C₁-C₄alkyl and —C₁-C₄ alkyl;

R^(b) is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl;

G is selected from the group consisting of —O—, —S—, and —CH₂—;

D is selected from the group consisting of a bond, —(CR^(a) ₂)—, and—C(O)—;

n is an integer from 0-2;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c); with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(c) is independently selected from the group consisting ofhydrogen, —CH₃, —C(O)—CH₃, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, —CH₃, —CF₃, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e),

R⁴ is selected from the group consisting of hydrogen, halogen, andoptionally substituted —C₁-C₆ alkyl;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂),heterocycloalkyl, or R^(f) and R^(g) may together form an optionallysubstituted heterocyclic ring, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, optionally substituted phenyl, and —C(O)OR^(b);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another embodiment of the compound of Formula Iv:

A is selected from the group consisting of —NR^(i)—, —O—, and —S—;

B is selected from the group consisting of —CR^(b)—, and —N—;

R^(i) is selected from the group consisting of hydrogen, —C(O)C₁-C₄alkyl and —C₁-C₄ alkyl;

R^(b) is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl;

G is selected from the group consisting of —O—, —S—, and —CH₂—;

D is selected from the group consisting of a bond, —(CH₂)—, and —C(O)—;

n is an integer from 0-2;

R¹ and R² are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with the proviso that atleast one of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl,optionally substituted —CH(OH)aryl, optionally substituted—(CH₂)cycloalkyl, optionally substituted —CH(OH)cycloalkyl, optionallysubstituted —(CH₂)heterocycloalkyl, optionally substituted—CH(OH)heterocycloalkyl, —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, F, Cl, Br, iodo,and CH₃;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂)_(n)cycloalkyl,and optionally substituted —(CH₂)_(n)heterocycloalkyl, or R^(f) andR^(g) may together form an optionally substituted heterocyclic ring,said heterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In a further aspect, the invention relates to the use of a compound ofFormula V:

wherein:

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b)——(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(n)—CR^(b)═CR^(b)—,—(CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—,—S(CR^(b) ₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—,—N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(m)C(R^(b))(NR^(b)R^(c))—,—C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b)₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—O—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(c))—S—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a)₂)—;

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c)C, optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhalogen, optionally substituted —C₁-C₄ alkyl, optionally substituted—S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl, optionallysubstituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F,optionally substituted —O—C₁-C₃ alkyl, and cyano;

R⁸ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃alkyl, optionally substituted —C₂-C₄ alkenyl, optionally substituted—C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted-O—C₁-C₃ alkyl, hydroxy, —(CR^(a) ₂)aryl, —(CR^(a)₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl,—C(O)heterocycloalkyl, —C(O)alkyl and cyano;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))-cycloalkyl,—C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),—SR^(d), S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g),—C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(═O)₂R^(e), —N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)naryl, optionally substituted —(CR^(a) ₂)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂),aryl, optionally substituted —(CR^(b)₂),cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring of 3-8 atoms containing 0-4unsaturations, which may contain a second heterogroup selected from thegroup consisting of O, NR^(c), and S, wherein said optionallysubstituted heterocyclic ring may be substituted with 0-4 substituentsselected from the group consisting of optionally substituted —C₁-C₄alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F, optionally substitutedphenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl; or

R³ and R⁸ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 to 6 atoms with0-2 unsaturations, not including the unsaturation on the ring to whichR³ and R⁸ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom; or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring comprising—CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N—;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or

R³ and R⁵ are taken together along with the carbons they are attached toform a ring of 5 to 6 atoms with 0-2 unsaturations, not including theunsaturation on the ring to which R³ and R⁵ are attached, including 0 to2 heteroatoms independently selected from —NR^(i)—, —O—, and —S—, withthe proviso that when there are 2 heteroatoms in the ring and bothheteroatoms are different than nitrogen then both heteroatoms have to beseparated by at least one carbon atom;

R⁷ is selected from the group consisting of hydrogen, halogen, amino,hydroxyl, —O—C₁-C₄ alkyl, —SH and —S—C₁-C₄ alkyl; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In one embodiment of the compound of Formula V:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

T is selected from the group consisting of —(CR^(a) ₂)_(n)—, —O(CR^(b)₂)(CR^(a) ₂)_(p)—, —S(CR^(b) ₂)(CR^(a) ₂)_(p)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(p)—, —N(R^(b))C(O)(CR^(a) ₂)_(p)—, —(CR^(a)₂)CH(NR^(b)R^(c))—, and —C(O)NH(CR^(b) ₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c); with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(e) is independently selected from the group consisting ofhydrogen , —CH₃, —C(O)—CH₃, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, —CH₃, —CF₃, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen;

R⁸ is selected from the group consisting of hydrogen, halogen, —CH₃,—CF₃, and cyano;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e),

R⁴ is selected from the group consisting of hydrogen, halogen, andoptionally substituted —C₁-C₆ alkyl;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring, said heterocyclic ring maycontain a second heterogroup within the ring selected from the groupconsisting of O, NR^(c), and S, wherein said optionally substitutedheterocyclic ring may be substituted with 0-4 substituents selected fromthe group consisting of optionally substituted —C₁-C₄ alkyl, —OR^(b),oxo, cyano, —CF₃, optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

R⁷ is selected from the group consisting of hydrogen, halogen, amino,hydroxyl, —O—CH₃, —SH and —S—CH₃; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another embodiment of the compound of Formula V:

G is selected from the group consisting of —O—, —S, and —CH₂;

T is selected from the group consisting of a bond, —(CH₂)_(n)—, —OCH₂—,—SCH₂—, —NHCH₂—, —NHC(O)(CH₂)_(p)—, —(CH₂)CH(NH₂)—, and —C(O)NH(CH₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

R¹ and R² are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with the proviso that atleast one of R¹ and R² is not hydrogen;

R⁸ is selected from the group consisting of hydrogen, halogen, —CH₃,—CF₃, and cyano;

R³ selected from the group consisting of hydrogen, halogen, optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl, optionallysubstituted —CH(OH)aryl, optionally substituted —(CH₂)cycloalkyl,optionally substituted —CH(OH)cycloalkyl, optionally substituted—(CH₂)heterocycloalkyl, optionally substituted —CH(OH)heterocycloalkyl,—S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, F, Cl, Br, iodo,and CH₃;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂)_(n)cycloalkyl,and optionally substituted —(CH₂)_(n)heterocycloalkyl, or R^(f) andR^(g) may together form an optionally substituted heterocyclic ring,said heterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(b) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

R⁷ is selected from the group consisting of hydrogen, F, Cl, amino,hydroxyl, and —O—CH₃; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another aspect, the invention relates to the use of a compound ofFormula VI:

wherein:

T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a)₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—, —S(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—,—N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(m)C(O)NR^(b)R^(c))—,—C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b)₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—O—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(a) ₂)_(p)—(CH^(b) ₂)—N(R^(c))—(CR^(b) ₂)— and—(CH₂)_(p)C(O)N(R^(b))C(R^(a) ₂)—;

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano; withthe proviso that at least one of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen, —CF₃,—CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(m)aryl,optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionally substituted—(CR^(a) ₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl,—C(R^(b))═C(R^(b))-cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl,—C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a)₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(g)R^(g), —C(O)OR^(h),—C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(═O)₂R^(e), —N(R^(b))S(═O)₂N^(g)R⁹, and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring of 3-8 atoms containing 0-4unsaturations, said heterocyclic ring may contain a second heterogroupwithin the ring selected from the group consisting of O, NR^(c), and S,wherein said optionally substituted heterocyclic ring may be substitutedwith 0-4 substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In one embodiment of the compound of Formula VI

T is selected from the group consisting of —(CR^(a) ₂)_(n)—, —O(CR^(b)₂)(CR^(a) ₂)_(p)—, —S(CR^(b) ₂)(CR^(a) ₂)_(p)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(p)—, —N(R^(b))C(O)(CR^(a) ₂)_(p)—, —(CR^(a)₂)C(R^(b))(NR^(b)R^(c))—, and —C(O)N(R^(b))(CR^(b) ₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c); with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(c) is independently selected from the group consisting ofhydrogen and —CH₃, —C(O)—CH₃, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, —CH₃, —CF₃, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring, said heterocyclic ring maycontain a second heterogroup within the ring selected from the groupconsisting of O, NR^(c), and S, wherein said optionally substitutedheterocyclic ring may be substituted with 0-4 substituents selected fromthe group consisting of optionally substituted —C₁-C₄ alkyl, —OR^(b),oxo, cyano, —CF₃, optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR¹²),heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another embodiment of the compound of Formula VI:

T is selected from the group consisting of a bond, —(CH₂)_(n)—, —OCH₂—,—SCH₂—, —NHCH₂—, —NHC(O)(CH₂)_(p)—, —(CH₂)CH(NH₂)_(p)—, and—C(O)NH(CH₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

R¹ and R² are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with the proviso that atleast one of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl,optionally substituted —CH(OH)aryl, optionally substituted—(CH₂)cycloalkyl, optionally substituted —CH(OH)cycloalkyl, optionallysubstituted —(CH₂)heterocycloalkyl, optionally substituted—CH(OH)heterocycloalkyl, —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), and —C(O)R^(e);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂)_(n)cycloalkyl,and optionally substituted —(CH₂)_(n)heterocycloalkyl, or R^(f) andR^(g) may together form an optionally substituted heterocyclic ring,said heterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In a further aspect, the invention relates to the use of a compound ofFormula VII:

wherein:

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b) (CR^(a) ₂)_(n)—, —S(CR^(a) ₂)_(n)—CR^(b)═CR^(b)—,—(CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—,—S(CR^(b) ₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—,—N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(n)C(R^(b))(NR^(b)R^(c))—,—C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b)₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—O—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a)₂)—;

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano; withthe proviso that at least one of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen, —CF₃,—CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(m)aryl,optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionally substituted—(CR^(a) ₂)_(m)heterocycloalyl, —C(R^(b))═C(R^(b))-aryl,—C(R^(b))═C(R^(b))— cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl,—C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a)₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h),—C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(═O)₂R^(e), —N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(g)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR²)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂),heterocycloalkyl, or R^(f) and R^(g) may together form an optionallysubstituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations,said heterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S. wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R⁵ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;

R⁹ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃alkyl, optionally substituted —C₂-C₄ alkenyl, optionally substituted—C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —O—C₁-C₃ alkyl, hydroxy, —(CR^(a) ₂)aryl, —(CR^(a)₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl,—C(O)heterocycloalkyl, —C(O)alkyl and cyano; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In one embodiment of the compound of Formula VII:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

T is selected from the group consisting of —(CR^(a) ₂)_(n)—, —O(CR^(b)₂)(CR^(a) ₂)_(p)—, —S(CR^(b) ₂)(CR^(a) ₂)_(p)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(p)—, —N(R^(b))C(O)(CR^(a) ₂)_(p)—, —(CR^(a)₂)C(R^(b))(NR^(b)R^(c))—, and —C(O)N(R^(b))(CR^(b) ₂);

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c); with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(c) is independently selected from the group consisting ofhydrogen, —CH₃, —C(O)—CH₃, and —C(O)H;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, —CH₃, —CF₃, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring, said heterocyclic ring maycontain a second heterogroup within the ring selected from the groupconsisting of O, NR^(c), and S, wherein said optionally substitutedheterocyclic ring may be substituted with 0-4 substituents selected fromthe group consisting of optionally substituted —C₁-C₄ alkyl, —OR^(b),oxo, cyano, —CF₃, optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

R⁹ is selected from the group consisting of optionally substituted—C₁-C₄ alkyl, —(CR^(a) ₂)aryl, C(O)aryl and C(O)alkyl; and

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In another embodiment of the compound of Formula VII:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

T is selected from the group consisting of a bond, —(CH₂)_(n)—, —OCH₂—,—SCH₂—, —NHCH₂—, —NHC(O)(CH₂)_(p)—, —(CH₂)CH(NH₂)—, and —C(O)NH(CH₂)—;

n is an integer from 0-2;

p is an integer from 0-1;

R¹ and R² are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with the proviso that atleast one of R¹ and R² is not hydrogen;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl,optionally substituted —CH(OH)aryl, optionally substituted—(CH₂)cycloalkyl, optionally substituted —CH(OH)cycloalkyl, optionallysubstituted —(CH₂)heterocycloalkyl, optionally substituted—CH(OH)heterocycloalkyl, —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), and —C(O)R^(e);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂),aryl, optionallysubstituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂)_(n)cycloalkyl,and optionally substituted —(CH₂)_(n)heterocycloalkyl, or R^(f) andR^(g) may together form an optionally substituted heterocyclic ring,said heterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

R⁹ is selected from the group consisting of optionally substituted—C₁-C₄ alkyl, —CH₂-aryl, C(O)aryl and C(O)alkyl;

X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates known in the art, phosphonic acid, phosphonic acid monoester,phosphinic acid, or a prodrug thereof.

In a further aspect, the invention relates to the use of a compound ofFormula VIII:

wherein:

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(—CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-, orCH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

A and T are each independently selected from the group consisting of—(CR^(a) ₂)—, —(CR^(a) ₂)₂—, —O(CR^(b) ₂)—, —S(CR^(b) ₂)—,—N(R^(c))(CR^(b) ₂)—, —N(R^(b))C(O)—, —C(O)(CR^(a) ₂)—, —(CR^(a)₂)C(O)—, —(CR^(b) ₂)O—, —(CR^(b) ₂)S—, and —(CR^(b) ₂)N(R^(c))—;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹, R², and R⁷ are each independently selected from the group consistingof hydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano; withthe proviso that at least one of R¹ and R² is not hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, hydroxy, —(CR^(a)₂)aryl, —(CR^(a) ₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl,—C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))— cycloalkyl,—(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),—SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e),—N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n)heterocyclo alkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring of 3-8 atoms containing 0-4unsaturations, said heterocyclic ring may contain a second heterogroupwithin the ring selected from the group consisting of O, NR^(c), and S,wherein said optionally substituted heterocyclic ring may be substitutedwith 0-4 substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl; or

R³ and R⁸ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 to 6 atoms with0-2 unsaturations, not including the unsaturation on the ring to whichR³ and R⁵ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom; or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R¹ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;

Y is selected from the group consisting of —O—, and —NR^(v)—;

when Y is —O—, R¹¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substitutedCH₂-heterocycloalkyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R^(z))₂OC(O)NR^(z)₂, —NR^(z)—C(O)—R^(y), —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y),—C(R^(z))₂OC(O)SR^(y), -alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy;

when Y is —NR^(v)—, then R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —[C(R^(z))₂]_(q)—C(O)OR^(y),—C(R^(x))₂C(O)OR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-C(O)OR^(y);

m is an integer from 0-3;

n is an integer from 0-2;

q is an integer 2 or 3;

Each R^(z) is selected from the group consisting of R^(y) and —H;

Each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;

Each R^(x) is independently selected from the group consisting of —H,and alkyl, or together R^(x) and R^(x) form a cycloalkyl group;

Each R^(V) is selected from the group consisting of —H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In one embodiment of the compound of Formula VIII:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

A and T are each independently selected from the group consisting of—(CR^(a) ₂)—, —(CR^(a) ₂)₂—, —O(CR^(b) ₂)—, —S(CR^(b) ₂)—,—(R^(c))(CR^(b) ₂)—, —N(R^(b))C(O)—, —C(O)(CR^(a) ₂)—, —(CR^(a) ₂)C(O)—,—(CR^(b) ₂)O—, —(CR^(b) ₂)S—, and —(CR^(b) ₂)N(R^(c))—;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c) with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(c) is independently selected from the group consisting ofhydrogen and —CH₃, —C(O)—CH₃, and —C(O)H;

R¹, R², and R⁷ are each independently selected from the group consistinghydrogen, halogen, —CH₃, —CF₃, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen;

-   -   R⁸ and R⁹ are each independently selected from the group        consisting of hydrogen, halogen, —CH₃, —CF₃, (CR^(a) ₂)aryl,        C(O)aryl, C(O)alkyl and cyano;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, halogen, andoptionally substituted —C₁-C₆ alkyl;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring, said heterocyclic ring maycontain a second heterogroup within the ring selected from the groupconsisting of O, NR^(c), and S, wherein said optionally substitutedheterocyclic ring may be substituted with 0-4 substituents selected fromthe group consisting of optionally substituted —C₁-C₄ alkyl, —OR^(b),oxo, cyano, —CF₃, optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl; or

R³ and R⁸ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R¹ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═; R⁵ is selected from the group consisting of —OH, —OCH₃,—OC(O)R^(e), —OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

Y is selected from the group consisting of —O—, and —NR^(v)—;

when Y is —O—, R¹¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, —C(R^(z))₂—OC(O)R^(y),—C(R^(z))₂—O—C(O)OR^(y), and -alkyl-S—C(O)R^(y);

when Y is —NR^(v)—, then R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —C(R^(z))₂—COOR^(y), and—C(R^(x))₂COOR^(y);

Each R^(z) is selected from the group consisting of R^(y) and —H;

Each R^(y) is selected from the group consisting of alkyl and aryl;

Each R^(x) is independently selected from the group consisting of —H andalkyl;

Each R^(V) is selected from the group consisting of —H and lower alkyl;

and pharmaceutically acceptable salts of said prodrugs andpharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In one embodiment of the compound of Formula VIII:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

A and T are each independently selected from the group consisting of—CH₂—, —(CH₂)₂—, —OCH₂—, —SCH₂—, —NH(CH₂)—, —NHC(O)—, —C(O)CH₂—,—CH₂C(O)—, —CH₂O—, —CH₂S—, and —CH₂)NH—;

R¹, R², and R⁷ are each independently selected from the group consistinghydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with the proviso that atleast one of R¹ and R² is not hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, (CH₂)aryl, C(O)aryl, C(O)alkyl;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl,optionally substituted —CH(OH)aryl, optionally substituted—(CH₂)cycloalkyl, optionally substituted —CH(OH)cycloalkyl, optionallysubstituted —(CH₂)heterocycloalkyl, optionally substituted—CH(OH)heterocycloalkyl, —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), and —C(O)R^(K);

R⁴ is selected from the group consisting of hydrogen, F, Cl, Br, iodo,and CH₃;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂)_(n)cycloalkyl,and optionally substituted —(CH₂)_(n)heterocycloalkyl, or R^(f) andR^(g) may together form an optionally substituted heterocyclic ring,said heterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl; or

R³ and R¹ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 6 atoms with 2unsaturations, not including the unsaturation on the ring to which R³and R⁸ are attached, including 0 to 1 —N—; or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═; R⁵ is selected from the group consisting of —OH, —OCH₃,—OC(O)R^(e), —OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

Y is selected from the group consisting of —O—, and —NR^(v)—;

when Y is —O—, R¹¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, —CH₂—OC(O)R^(y), —CH(CH₃)—OC(O)R^(y),—CH₂—O—C(O)OR^(y), —CH(CH₃)—O—C(O)OR^(y), and —(CH₂)₂—S—C(O)R^(y);

when Y is —NR^(v)—, R¹¹ attached to —NR^(v)— is independently selectedfrom the group consisting of —H and —C(R^(x))₂COOR^(y);

Each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In a further aspect, the invention relates to the use of a compound ofFormula IX:

wherein:

G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—,—S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-, orCH₂ linked to any of the preceding groups;

or G is R⁵⁰-R⁵¹ wherein;

R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴;

R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,fluoromethyl, difluoromethyl, or trifluoromethyl;

R⁵³ is selected from hydrogen, halogen, hydroxyl, mercapto, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

R⁵² is selected from hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,methylthio, fluoromethylthio, difluoromethylthio andtrifluoromethylthio;

T is selected from the group consisting of —(CR^(a) ₂)_(n)C(R^(b) ₂)O—,—(CR^(a) ₂)_(n)C(R^(b) ₂)N(R^(b))—, —(CR^(a) ₂)_(n)C(R^(b) ₂)S—,—C(O)(CR^(a) ₂)_(p)C(R^(b) ₂)O—, —C(O)(CR^(a) ₂)_(p)C(R^(b) ₂)N(R^(b))—,—C(O)(CR^(a) ₂)_(p)C(R^(b) ₂)S—, —(CR^(a) ₂)_(p)C(O)C(R^(b) ₂)O—,—(CR^(a) ₂)_(p)C(O)C(R^(b) ₂)N(R^(b))—, and —(CR^(a) ₂)_(p)C(O)C(R^(b)₂)S—,

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl —NR^(b)R^(c)C, optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹, R², R⁶, and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, optionally substituted —C₁-C₄ alkyl,optionally substituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano;with the proviso that at least one of R¹ and R² is not hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, hydroxy, —(CR^(a)₂)aryl, —(CR^(a) ₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl,—C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano; or

R¹ and R⁷ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 to 6 atoms with0-2 unsaturations, not including the unsaturation on the ring to whichR¹ and R⁷ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))— cycloalkyl, —C(R^(b))50C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),—SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e),—N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

Each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g);

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl , andoptionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl,

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring of 3-8 atoms containing 0-4unsaturations, said heterocyclic ring may contain a second heterogroupwithin the ring selected from the group consisting of O, NR^(c), and S,wherein said optionally substituted heterocyclic ring may be substitutedwith 0-4 substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl; or

R³ and R⁸ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 to 6 atoms with0-2 unsaturations, not including the unsaturation on the ring to whichR³ and R⁵ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom; or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═, —N═CH—CH═, —CH—N—CH═ or —CH—CH—N═;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h),—OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations not including the unsaturation on the ring to which R³ andR⁵ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;

X is P(O)(YR¹¹)Y″;

Y″ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionally substituted(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k) S(═O)R^(e), —(CR^(a)₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), and —(CR^(a) ₂)_(k)C(O)R^(e);

Y is selected from the group consisting of —O—, and —NR^(c)—;

when Y is —O—, R¹¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂,—NR^(z)C(O)—R^(y), —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y),—C(R^(z))₂OC(O)SR^(y), -alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy;

when Y is —NR^(v)—, then R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —[C(R^(z))₂]_(q)—C(O)OR^(y),—C(R^(x))₂C(O)OR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-C(O)OR^(y);

q is an integer 2 or 3;

Each R^(z) is selected from the group consisting of R^(y) and —H;

Each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;

Each R^(x) is independently selected from the group consisting of —H,and alkyl, or together R^(x) and R^(x) form a cycloalkyl group;

Each R^(V) is selected from the group consisting of —H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In one embodiment of the compound of Formula IX:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

T is selected from the group consisting of —(CR^(a) ₂)_(n)C(R^(b) ₂)O—,—(CR^(a) ₂)_(n)C(R^(b) ₂)N(R^(b))—, and —(CR^(a) ₂)_(n)C(R^(b) ₂)S—;

k is an integer from 0-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

Each R^(a) is independently selected from the group consisting ofhydrogen, —CH₃, halogen, —OH, —OCH₃, —OCF₃, and —NR^(b)R^(c); with theproviso that when one R^(a) is attached to C through an O, S, or N atom,then the other R^(a) attached to the same C is a hydrogen, or attachedvia a carbon atom;

Each R^(b) is independently selected from the group consisting ofhydrogen and —CH₃;

Each R^(c) is independently selected from the group consisting ofhydrogen and —CH₃, —C(O)—CH₃, and —C(O)H;

R¹, R², R⁶, and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, —CH₃, —CF₃, and cyano; with the provisothat at least one of R¹ and R² is not hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, halogen, —CH₃, —CF₃, (CR^(a) ₂)aryl, C(O)aryl, C(O)alkyl andcyano; or

R¹ and R⁷ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 atoms with 0-1unsaturations, not including the unsaturation on the ring to which R¹and R⁷ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, halogen, andoptionally substituted —C₁-C₆ alkyl;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(a) ₂)_(n)aryl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b)₂)_(n)cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form anoptionally substituted heterocyclic ring, said heterocyclic ring maycontain a second heterogroup within the ring selected from the groupconsisting of O, NR^(c), and S, wherein said optionally substitutedheterocyclic ring may be substituted with 0-4 substituents selected fromthe group consisting of optionally substituted —C₁-C₄ alkyl, —OR^(b),oxo, cyano, —CF₃, optionally substituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl; or

R³ and R⁸ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R⁸ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

X is P(O)(YR¹¹)Y″;

Y″ is hydrogen, optionally substituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F,—CH₂OH, —(CR^(a) ₂)_(k)S(═O)₂N^(f)R^(g), or —(CR^(a)₂)_(k)C(O)NR^(g)R^(g);

Y is selected from the group consisting of —O—, and —NR^(v)—,

when Y is —O—, R¹¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, —C(R^(z))₂—OC(O)R^(y),—C(R^(z))₂—O—C(O)OR^(y), and -alkyl-S—C(O)R^(y);

when Y is —NR^(v)—, then R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —(R^(z))₂—C(O)OR^(y), and—C(R^(x))₂C(O)OR^(y);

Each R^(z) is selected from the group consisting of R^(y) and —H;

Each R^(y) is selected from the group consisting of alkyl and aryl;

Each R^(x) is independently selected from the group consisting of —H andalkyl;

Each R^(V) is selected from the group consisting of —H and lower alkyl;

and pharmaceutically acceptable salts of said prodrugs andpharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In one embodiment of the compound of Formula IX:

G is selected from the group consisting of —O—, —S—, and —CH₂—;

T is selected from the group consisting of —CH₂CH₂O—, —CH₂CH₂NH—, and—CH₂CH₂S—;

R¹, R², R⁶, and R⁷ are each independently selected from the groupconsisting of hydrogen, Cl, Br, I, —CH₃, —CF₃, and cyano; with theproviso that at least one of R¹ and R² is not hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, Cl, Br, I, —CH₃, —CF₃, (CH₂)aryl, C(O)aryl, C(O)alkyl; or

R¹ and R⁷ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 5 atoms with 0unsaturations, not including the unsaturation on the ring to which R¹and R⁷ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;

R³ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₆ alkyl, optionally substituted —(CH₂)aryl,optionally substituted —CH(OH)aryl, optionally substituted—(CH₂)cycloalkyl, optionally substituted —CH(OH)cycloalkyl, optionallysubstituted —(CH₂)heterocycloalkyl, optionally substituted—CH(OH)heterocycloalkyl, —S(═O)₂R^(e), —S(═O)₂N^(f)R^(g),—C(O)NR^(f)R^(g), and —C(O)R^(e);

R⁴ is selected from the group consisting of hydrogen, F, Cl, Br, iodo,and CH₃;

Each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —(CH₂)_(n)aryl, optionally substituted —(CH₂)_(n)cycloalkyl,and optionally substituted —(CH₂),heterocycloalkyl, or R^(f) and R^(g)may together form an optionally substituted heterocyclic ring, saidheterocyclic ring may contain a second heterogroup within the ringselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(e), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

Each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₆ alkyl, optionally substituted —(CH₂)_(n)aryl,optionally substituted —(CH₂)_(n)cycloalkyl, and optionally substituted—(CH₂)_(n)heterocycloalkyl; or

R³ and R¹ are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of 6 atoms with 2unsaturations, not including the unsaturation on the ring to which R³and R⁵ are attached, including 0 to 1 —N—; or

R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═;

R⁵ is selected from the group consisting of —OH, —OCH₃, —OC(O)R^(e),—OC(O)OR^(e), and —NHC(O)R^(e); or

R³ and R⁵ are taken together along with the carbons they are attached toform an optionally substituted ring of 5 atoms with 1 unsaturation, notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom;

X is P(O)(YR¹¹)Y″;

Y″ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₃-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH,—(CH₂)_(p)S(═O)₂NH₂, —(CH₂)_(p)C(O)NH₂, —(CH₂)_(k)C(O)OH, and—(CH₂)_(k)C(O)OCH₃;

Y is selected from the group consisting of —O—, and —NR^(v)—;

when Y is —O—, R¹¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, —CH₂—OC(O)R^(y), —CH(CH₃)—OC(O)R^(y),—CH₂—O—C(O)OR^(y), —CH(CH₃)—O—C(O)OR^(y), and —(CH₂)₂—S—C(O)R^(y);

when Y is —NR^(v)—, R¹¹ attached to —NR^(v)— is independently selectedfrom the group consisting of —H and —C(R^(x))₂C(O)OR^(y);

Each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In one embodiment of the compound of Formula II, III, IV, V, VI, VII, orIX:

X is P(O)(YR¹¹)(Y′R¹¹) or P(O)(YR¹¹)Y″;

Y″ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k) S(═O)R^(e), —(CR^(a)₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), and —(CR^(a) ₂)_(k)C(O)R^(e);

Y and Y′ are each independently selected from the group consisting of—O—, and —NR^(v)—;

when Y is —O— and Y″ is hydrogen, optionally substituted —C₁-C₆-alkyl,—CF₃, —CHF₂, —CH₂F, —CH₂OH, optionally substituted —C₂-C₆ alkenyl,optionally substituted —C₂-C₆ alkynyl, optionally substituted —(CR^(a)₂)_(n)aryl, optionally substituted —(CR2)ncycloalkyl, optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e),—(CR^(a) ₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), —(CR^(a) ₂)_(k)C(O)OR^(h), or —(CR^(a)₂)_(k)C(O)R^(e), or when Y and Y′ are both —O—, R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy;

when Y is —NR^(v)— and Y″ is hydrogen, optionally substituted—C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionally substituted —C₂-C₆alkenyl, optionally substituted —C₂-C₆ alkynyl, optionally substituted—(CR^(a) ₂)_(n)aryl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl,optionally substituted —(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a)₂)_(k)S(═O)R^(e), —(CR^(a) ₂)_(k)S(═O)₂R^(e), —(CR^(a)₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a) ₂)_(k)C(O)NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)OR^(h), -or (CR^(a) ₂)_(k)C(O)R^(e), or when Y and Y′ are both—NR^(v)—, then R¹¹ attached to —NR^(v)— is independently selected fromthe group consisting of —H, —[C(R^(z))₂]_(q)—C(O)OR^(y),—C(R^(x))₂C(O)OR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-C(O)OR^(y);

when Y is —O— and Y₁ is NR^(v), then R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; and R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —[C(R^(z))₂]_(q)—C(O)OR^(y),—C(R^(x))₂C(O)OR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-COOR^(y);

or when Y and Y′ are independently selected from —O— and —NR^(v)—, thenR¹¹ and R¹¹ together form a cyclic group comprising -alkyl-S—S-alkyl-,or together R¹¹ and R¹¹ are the group:

wherein:

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted I-alkenyl, and optionally substitutedI-alkynyl; or

together V and Z are connected via an additional 3-5 atoms to form acyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms andthe remaining atoms are carbon, substituted with hydrogen, hydroxy,acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxyattached to a carbon atom that is three atoms from both Y groupsattached to the phosphorus; or

together V and Z are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon or carbon substituted by hydrogen, that is fused to an arylgroup at the beta and gamma position to the Y attached to thephosphorus; or

together V and W are connected via an additional 3 carbon atoms to forman optionally substituted cyclic group containing 6 carbon atoms orcarbon substituted by hydrogen and substituted with one substituentselected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy,attached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

together Z and W are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon or carbon substituted by hydrogen, and V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl; or

together W and W′ are connected via an additional 2-5 atoms to form acyclic group, wherein O₂ atoms are heteroatoms and the remaining atomsare carbon or carbon substituted by hydrogen, and V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

Z is selected from the group consisting of —CHR^(z)OH,—CHR^(z)OC(O)R^(y), —CHR^(a)OC(S)R^(y), —CHR^(z)OC(S)OR^(y),—CHR^(z)OC(O)SR^(y), —CHR^(Z)OCO₂R^(y), —OR^(z), —SR^(z), —CHR^(z)N₃,—CH₂aryl, —CH(aryl)OH, —CH(CH═CR^(z) ₂)OH, —CH(C≡CR^(z))OH, —R^(z),—NR^(z) ₂, —OCOR^(y), —OCO₂R^(y), —SCOR^(y), —SCO₂R^(y), —NHCOR^(z),—NHCO₂R^(y), —CH₂NHaryl, (CH₂)_(q)—OR², and —(CH₂)_(q)—SR^(z);

q is an integer 2 or 3;

Each R^(z) is selected from the group consisting of R^(y) and —H;

Each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;

Each R^(x) is independently selected from the group consisting of —H,and alkyl, or together R^(x) and R^(x) form a cycloalkyl group;

Each R^(V) is selected from the group consisting of —H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;

with the provisos that:

a) V, Z, W, W′ are not all —H; and

b) when Z is —R^(z), then at least one of V, W, and W′ is not —H, alkyl,aralkyl, or heterocycloalkyl;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In another embodiment of the compound of Formula II, III, rV, V, VI,VII, or IX:

X is P(O)(YR¹¹)(Y′R¹¹) or P(O)(YR¹¹)Y″;

Y″ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e), —(CR^(a)₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), and —(CR^(a) ₂)_(k)C(O)R^(e);

Y and Y′ are each independently selected from the group consisting of—O—, and —NR^(v)—;

when Y is —O— and Y″ is hydrogen, optionally substituted —C₁-C₆-alkyl,—CF₃, —CHF₂, —CH₂F, —CH₂OH, —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), or—(CR^(a) ₂)_(k)C(O)NR^(f)R^(g), or when Y and Y′ are both —O—, R¹¹attached to —O— is independently selected from the group consisting of—H, alkyl, —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), and-alkyl-S—C(O)R^(y);

when Y is —NR^(v)— and Y″ is hydrogen, optionally substituted—C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, —(CR^(a)₂)_(k)S(═O)₂NR^(f)R^(g), or —(CR^(a) ₂)_(k)C(O)NR^(f)R^(g), or when Yand Y′ are both —NR^(v)—, then R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —C(R^(z))₂—C(O)OR^(y), and—C(R^(x))₂C(O)OR^(y);

when Y is —O— and Y′ is NR^(v), then R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, —C(R^(z))₂—OC(O)R^(y),—C(R^(z))₂—O—C(O)OR^(y), and -alkyl-S—C(O)R^(y); and R¹¹ attached to—NR^(v)— is independently selected from the group consisting of —H,—C(R^(z))₂—C(O)OR^(y), and —C(R^(x))₂C(O)OR^(y);

or when Y and Y′ are independently selected from —O— and —NR^(v)—, thentogether R¹¹ and R¹¹ are the group:

wherein:

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

Z is hydrogen

Each R^(z) is selected from the group consisting of R^(y) and —H;

Each R^(y) is selected from the group consisting of alkyl and aryl;

Each R^(x) is independently selected from the group consisting of —H andalkyl;

Each R^(V) is selected from the group consisting of —H and lower alkyl;

with the provisos that:

a) V, Z, W, W′ are not all —H; and

b) when Z is —R^(z), then at least one of V, W, and W′ is not —H, alkyl,aralkyl, or heterocycloalkyl;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In another embodiment of the compound of Formula II, III, IV, V, VI,VII, or VIII:

X is P(O)(YR¹¹)(Y′R¹¹) or P(O)(YR¹¹)Y″;

Y″ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CW2).cycloalkyl, optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e), —(CR^(a)₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g),—(CW2)_(k)C(O)NR^(f)R^(g), and —(CR^(a) ₂)_(k)C(O)R^(e);

Y and Y′ are each independently selected from the group consisting of—O—, and —NR^(v)—;

when Y is —O— and Y″ is hydrogen, optionally substituted —C₁—C-alkyl,—CF₃, —CHF₂, —CH₂F, —CH₂OH, —(CH₂)_(p)S(═O)₂NH₂, —(CH₂)_(p)C(O)NH₂, or—(CR^(a) ₂)_(k)C(O)OCH₃, or when Y and Y′ are both —O—, R¹¹ attached to—O— is independently selected from the group consisting of —H, alkyl,—CH₂—OC(O)R^(y), —CH(CH₃)—OC(O)R^(y), —CH₂—O—C(O)OR^(y),—CH(CH₃)—O—C(O)OR^(y), and —(CH₂)₂—S—C(O)R^(y);

when Y is —NR^(v)— and Y″ is hydrogen, optionally substituted—C₁—C-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, —(CH₂)_(p)S(═O)₂NH₂,—(CH₂)_(p)C(O)NH₂, or —(CR^(a) ₂)_(k)C(O)OCH₃, or when Y and Y′ are both—NR^(v)—, then R¹¹ attached to —NR^(v)— is independently selected fromthe group consisting of —H and —C(R^(x))₂C(O)OR^(y);

when Y is —O— and Y₁ is NR^(v), then R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl, andoptionally substituted aryl, and R¹¹ attached to —NR^(v)— isindependently selected from the group consisting of —H and—C(R^(x))₂C(O)OR^(y);

or when Y and Y′ are independently selected from —O— and —NR^(v)—, thentogether R¹¹ and R¹¹ are the group:

wherein:

V is aryl;

W, W′ and Z are hydrogen;

Each R^(y) is selected from the group consisting of t-butyl, iso-propyl,ethyl, and methyl;

Each R^(x) is independently selected from the group consisting of —H and—CH₃;

Each R^(v) is —H;

and pharmaceutically acceptable salts and prodrugs thereof andpharmaceutically acceptable salts of said prodrugs.

In one aspect, the compound of Formula I-IX is selected from the groupconsisting of:

and monoesters thereof, and prodrugs of the compounds or the monoestersof the compounds, and pharmaceutically acceptable salts thereof. In oneembodiment, the prodrugs are bis-POM, carbonate, bisamidate, or4-aryl-2-oxo-2-λ⁵-1,3,2-dioxaphosphonane prodrugs of the compounds orbis-POM, carbonate, or bisamidate prodrugs of the monoesters of thecompounds.

In another aspect, the compound of Formula I-IX is selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.

In a further aspect, the compound of Formula I-IX is selected from thegroup consisting of:

and pharmaceutically acceptable salts and prodrugs thereof. In oneembodiment, the prodrugs of the above listed compounds are POM ester,carbonate, or amidate prodrugs.

For all chemical structures pictured herein, when an oygen is depictedwith only a single bond to another atom, the presence of a hydrogenbonded to the oxygen is to be assumed. When a nitrogen is depicted withonly two bonds to one or more other atoms, the presence of a hydrogenbonded to the nitrogen is to be assumed.

Moreover, the compounds of the present invention can be administered incombination with other pharmaceutical agents that are used to lower thefat content of liver or pharmaceutical agents that are used to treat orprevent disorders that are related to or result in an increase in thefat content of liver.

The compounds of the present invention can be administered incombination with other pharmaceutical agents that are used to lowerserum cholesterol such as a cholesterol biosynthesis inhibitor or acholesterol absorption inhibitor, especially a HMG-CoA reductaseinhibitor, or a HMG-CoA synthase inhibitor, or a HMG-CoA reductase orsynthase gene expression inhibitor, a cholesteryl ester transfer protein(CETP) inhibitor (e.g., torcetrapib), a bile acid sequesterant (e.g.,cholestyramine (Questran®), colesevelam and colestipol (Colestid®)), ora bile acid reabsorption inhibitor (see, for example, U.S. Pat. No.6,245,744, U.S. Pat. No. 6,221,897, U.S. Pat. No. 6,277,831, EP 0683773, EP 0683 774), a cholesterol absorption inhibitor as described(e.g., ezetimibe, tiqueside, pamaqueside or see, e.g., in WO 0250027), aPPARalpha agonist, a mixed PPAR alpha/gamma agonist such as, forexample, AZ 242 (Tesaglitazar,(S)-3-(4-[2-(4-methanesulfony-loxyphenyl)ethoxy]phenyl)-2-ethoxypropionicacid), BMS 298585N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine)or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169,WO 96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO00/64876, a MTP inhibitor such as, for example, implitapide, a fibrate,an ACAT inhibitors (e.g., avasimibe), an angiotensin II receptorantagonist, a squalene synthetase inhibitor, a squalene epoxidaseinhibitor, a squalene cyclase inhibitor, combined squaleneepoxidase/squalene cyclase inhibitor, a lipoprotein lipase inhibitor, anATP citrate lyase inhibitor, lipoprotein(a) antagonist, an antioxidantor niacin (e.g., slow release niacin). The compounds of the presentinvention may also be administered in combination with a naturallyoccurring compound that act to lower plasma cholesterol levels. Suchnaturally occurring compounds are commonly called nutraceuticals andinclude, for example, garlic extract and niacin.

In one aspect, the HMG-CoA reductase inhibitor is from a class oftherapeutics commonly called statins. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR; see U.S. Pat. Nos. 4,231,938; 4,294,926; 4,319,039),simvastatin (ZOCOR; see U.S. Pat. Nos. 4,444,784; 4,450,171, 4,820,850;4,916,239), pravastatin (PRAVACHOL; see U.S. Pat. Nos. 4,346,227;4,537,859; 4,410,629; 5,030,447 and 5,180,589), lactones of pravastatin(see U.S. Pat. No. 4,448,979), fluvastatin (LESCOL; see U.S. Pat. Nos.5,354,772; 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853;5,290,946; 5,356,896), lactones of fluvastatin, atorvastatin (LIPITOR;see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952), lactonesof atorvastatin, cerivastatin (also known as rivastatin and BAYCHOL; seeU.S. Pat. No. 5,177,080, and European Application No. EP-491226A),lactones of cerivastatin, rosuvastatin (CRESTOR; see U.S. Pat. Nos.5,260,440 and RE37314, and European Patent No. EP521471), lactones ofrosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin,bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin,pitivastatin, mevastatin (see U.S. Pat. No. 3,983,140), and velostatin(also referred to as synvinolin). Other examples of HMG-CoA reductaseinhibitors are described in U.S. Pat. Nos. 5,217,992; 5,196,440;5,189,180; 5,166,364; 5,157,134; 5,110,940; 5,106,992; 5,099,035;5,081,136; 5,049,696; 5,049,577; 5,025,017; 5,011,947; 5,010,105;4,970,221; 4,940,800; 4,866,058; 4,686,237; 4,647,576; EuropeanApplication Nos. 0142146A2 and 0221025A1; and PCT Application Nos. WO86/03488 and WO 86/07054. Also included are pharmaceutically acceptableforms of the above. All of the above references are incorporated hereinby reference.

Non-limiting examples of suitable bile acid sequestrants includecholestyramine (a styrene-divinylbenzene copolymer containing quaternaryammonium cationic groups capable of binding bile acids, such as QUESTRANor QUESTRAN LIGHT cholestyramine which are available from Bristol-MyersSquibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl)alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Other usefulbile acid sequestrants are disclosed in PCT Patent Applications Nos. WO97/11345 and WO 98/57652, and U.S. Pat. Nos. 3,692,895 and 5,703,188which are incorporated herein by reference. Suitable inorganiccholesterol sequestrants include bismuth salicylate plus montmorilloniteclay, aluminum hydroxide and calcium carbonate antacids.

In the above description, a fibrate base compound is a medicament forinhibiting synthesis and secretion of triglycerides in the liver andactivating lipoprotein lipase, thereby lowering the triglyceride levelin the blood. Examples include bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, clofibric acid, ethofibrate,fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate,simfibrate and theofibrate. Such an ACAT inhibitor includes, forexample: a compound having the general formula (I) disclosed in WO92/09561 [e.g., FR-129169, of which the chemical name isN-(1,2-diphenylethyl)-2-(2-octyloxyphenyl)acetamide]; a compound havingthe general formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in the JapanesePatent Publication Kohyo) Hei 8-510256 (WO 94/26702, U.S. Pat. No.5,491,172) {e.g., CI-1011, of which the chemical name is2,6-diisopropylphenyl-N-[(2,4,6-triisopropylphenyl)acetyl]sulfamate, andin the present invention CI-1011 including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof}; a compound havingthe general formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in EP 421441 (U.S.Pat. No. 5,120,738) {e.g., F-1394, of which the chemical name is(1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexan-1-yl3-[(4R)—N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate,and in the present invention F-1394 including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof}; a compoundincluding a pharmacologically acceptable salt/co-crystal, ester orprodrug thereof disclosed in the Japanese Patent Publication (Kohyo)2000-500771 (WO 97/19918, U.S. Pat. No. 5,990,173) [e.g., F-12511, ofwhich the chemical name is(S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthio-α-phenylacetanilide, andin the present invention F-12511 including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof]; a compound havingthe general formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in the JapanesePatent Publication Kokai) Hei 10-195037 (EP 790240, U.S. Pat. No.5,849,732) [e.g., T-2591, of which the chemical name is1-(3-t-butyl-2-hydroxy-5-methoxyphenyl)-3-(2-cyclohexylethyl)-3-(4-dimethylaminophenyl)urea,and in the present invention T-2591 including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereofl; a compound havingthe general formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in WO 96/26948{e.g., FCE-28654, of which the chemical name is1-(2,6-diisopropylphenyl)-3-[(4R,5R)-4,5-di-methyl-2-(4-phosphonophenyl)-1,3-dioxolan-2-ylmethyl]urea,including a pharmacologically acceptable salt/co-crystal, ester orprodrug thereof}; a compound having the general formula (I) or apharmacologically acceptable salt thereof disclosed in the specificationof WO 98/54153 (EP 987254) {e.g., K-10085, of which the chemical name isN-[2,4-bis(methylthio)-6-methyl-3-pyridyl]-2-[4-[2-(oxazolo[4,5-b]pyridine-2-ylthio)ethyl]piperazin-1-yl]acetamide,including a pharmacologically acceptable salt/co-crystal, ester orprodrug thereof}; a compound having the general formula (I) disclosed inWO 92/09572 (EP 559898, U.S. Pat. No. 5,475,130) [e.g., HL-004, of whichthe chemical name isN-(2,6-diisopropylphenyl)-2-tetradecylthioacetamide]; a compound havingthe general formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in the JapanesePatent Publication (Kokai) Hei 7-82232 (EP 718281) {e.g., NTE-122, ofwhich the chemical name istrans-1,4-bis[1-cyclohexyl-3-(4-dimethylaminophenyl)ureidomethyl]cyclohexane,and in the present invention NTE-122 includes pharmacologicallyacceptable salts of NTE-122}; a compound including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof disclosed in theJapanese Patent Publication (Kohyo) Hei 10-510512 (WO 96/10559) {e.g.,FR-186054, of which the chemical name is1-benzyl-1-[3-(pyrazol-3-yl)benzyl]-3-[2,4-bis(methylthio)-6-methylpyridi-n-3-yl]urea, and in the present invention FR-186054 including apharmacologically acceptable salt/co-crystal, ester or prodrug thereof);a compound having the general formula (I) including a pharmacologicallyacceptable salt/co-crystal, ester or prodrag thereof disclosed in WO96/09287 (EP 0782986, U.S. Pat. No. 5,990,150) [e.g.,N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide, and inthe present invention including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof]; and a compound having thegeneral formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in WO 97/12860 (EP0866059, U.S. Pat. No. 6,063,806) [e.g.N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide,including a pharmacologically acceptable salt/co-crystal, ester orprodrug thereofl. The ACAT inhibitor preferably is a compound selectedfrom the group consisting of FR-129169, CI-1011, F-1394, F-12511,T-2591, FCE-28654, K-10085, HL-004, NTE-122, FR-186054,N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide(hereinafter referred to as compound A), andN-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide(hereinafter referred as compound B), including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof. The ACAT inhibitormore preferably is a compound selected from the group consisting ofCI-1011, F-12511,N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropancamide(compound A), andN-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide (compoundB), including a pharmacologically acceptable salt/co-crystal, ester orprodrug thereof; most preferred isN-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide(compound A).

An angiotensin II receptor antagonist includes, for example, a biphenyltetrazole compound or biphenylcarboxylic acid derivative such as: acompound having the general formula (I) including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof disclosed in theJapanese Patent Publication (Kokai) Sho 63-23868 (U.S. Pat. No.5,138,069) {e.g., losartan, of which the chemical name is2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazol-5-methanol,and in the present invention losartan including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof}; a compound havingthe general formula (I) including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in the JapanesePatent Publication (Kohyo) Hei 4-506222 (WO 91/14679) {e.g., irbesartan,of which the chemical name is2-N-butyl-4-spirocyclopentane-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-imidazoline-5-one,and in the present invention irbesartan including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof}; a compound havingthe general formula (I), an ester thereof, including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof disclosed in theJapanese Patent Publication (Kokai) Hei 4-235149 (EP 433983) {e.g.,valsartan, of which the chemical name is(S)—N-valeryl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]valine, and inthe present invention valsartan including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof}; a carhoxylic acid derivativehaving the general formula (I), including a pharmacologically acceptablesalt/co-crystal, ester or prodrug thereof disclosed in the JapanesePatent Publication (Kokai) Hei 4-364171 (U.S. Pat. No. 5,196,444) {e.g.,candesartan, of which the chemical name is1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzimidazole-7-carboxylate,and in the present invention candesartan including a pharmacologicallyacceptable salt/co-crystal, ester or prodrug thereof (TCV-116 or thelike), including a pharmacologically acceptable salt/co-crystal, esteror prodrug thereof}; a carboxylic acid derivative having the generalformula (I), including a pharmacologically acceptable salt/co-crystal,ester or prodrug thereof disclosed in the Japanese Patent Publication(Kokai) Hei 5-78328 (U.S. Pat. No. 5,616,599) {e.g., olmesartan, ofwhich the chemical name is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate,and in the present invention olmesartan includes carboxylic acidderivatives thereof, pharmacologically acceptable esters of thecarboxylic acid derivatives (CS-866 or the like), including apharmacologically acceptable salt/co-crystal, ester or prodrug thereof};and a compound having the general formula (I), including apharmacologically acceptable salt/co-crystal, ester or prodrug thereofdisclosed in the Japanese Patent Publication (Kokai) Hei 4-346978 (U.S.Pat. No. 5,591,762, EP 502,314) {e.g., telmisartan, of which thechemical name is4′-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate,including a pharmacologically acceptable salt/co-crystal, ester orprodrug thereof}. The angiotensin II receptor antagonist preferably islosartan, irbesartan, valsartan, candesartan, olmesartan, ortelmisartan; more preferred is losartan or olmesartan; and mostpreferred is olmesartan.

In addition to being useful in treating or preventing certain diseasesand disorders, combination therapy with compounds of this inventionmaybe useful in reducing the dosage of the second drug or agent (e.g.,atorvastatin).

In addition, the compounds of the present invention can be used incombination with an apolipoprotein B secretion inhibitor and/ormicrosomal triglyceride transfer protein (MTP) inhibitor. Someapolipoprotein B secretion inhibitors and/or MTP inhibitors aredisclosed in U.S. Pat. No. 5,919,795.

Any HMG-CoA reductase inhibitor may be employed as an additionalcompound in the combination therapy aspect of the present invention. Theterm HMG-CoA reductase inhibitor refers to a compound that inhibits thebiotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acidas catalyzed by the enzyme HMG-CoA reductase. Such inhibition may bedetermined readily by one of skill in the art according to standardassays (e.g., Meth. Enzymology 71:455-509 (1981); and the referencescited therein). A variety of these compounds are described andreferenced below. U.S. Pat. No. 4,231,938 discloses certain compoundsisolated after cultivation of a microorganism belonging to the genusAspergillus, such as lovastatin. Also U.S. Pat. No. 4,444,784 disclosessynthetic derivatives of the aforementioned compounds, such assimvastatin. Additionally, U.S. Pat. No. 4,739,073 discloses certainsubstituted indoles, such as fluvastatin. Further, U.S. Pat. No.4,346,227 discloses ML-236B derivatives, such as pravastatin. Inaddition, EP 491,226 teaches certain pyridyldihydroxyheptenoic acids,such as rivastatin. Also, U.S. Pat. No. 4,647,576 discloses certain6-[2-(substituted-pyrrol-1-yl)-alkyl]-pyran-2-ones such as atorvastatin.Other HMG-CoA reductase inhibitors will be known to those skilled in theart. Examples of currently or previously marketed products containingHMG-CoA reductase inhibitors include cerivastatin Na, rosuvastatin Ca,fluvastatin, atorvastatin, lovastatin, pravastatin Na and simvastatin.

Any HMG-CoA synthase inhibitor may be used as an additional compound inthe combination therapy aspect of this invention. The term HMG-CoAsynthase inhibitor refers to a compound that inhibits the biosynthesisof hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A andacetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Suchinhibition may be determined readily by one of skill in the artaccording to standard assays (e.g., Meth. Enzymology 35:155-160 (1975);and Meth. Enzymology, 110:19-26 (1985); and the references citedtherein). A variety of these compounds are described and referencedbelow. U.S. Pat. No. 5,120,729 discloses certain beta-lactamderivatives. U.S. Pat. No. 5,064,856 discloses certain spiro-lactonederivatives prepared by culturing the microorganism MF5253. U.S. Pat.No. 4,847,271 discloses certain oxetane compounds such as11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoicacid derivatives. Other HMG-CoA synthase inhibitors useful in themethods, compositions and kits of the present invention will be known tothose skilled in the art.

Any compound that decreases HMG-CoA reductase gene expression may beused as an additional compound in the combination therapy aspect of thisinvention. These agents may be HMG-CoA reductase transcriptioninhibitors that block the transcription of DNA or translation inhibitorsthat prevent translation of mRNA coding for HMG-CoA reductase intoprotein. Such inhibitors may either affect transcription or translationdirectly, or may be biotransformed into compounds that have theaforementioned attributes by one or more enzymes in the cholesterolbiosynthetic cascade or may lead to the accumulation of an isoprenemetabolite that has the aforementioned activities. Such regulation isreadily determined by those skilled in the art according to standardassays (Meth. Enzymology 110: 9-19 (1985)). Several such compounds aredescribed and referenced below; however, other inhibitors of HMG-CoAreductase gene expression will be known to those skilled in the art, forexample, U.S. Pat. No. 5,041,432 discloses certain 15-substitutedlanosterol derivatives that are inhibitors of HMG-CoA reductase geneexpression. Other oxygenated sterols that suppress the biosynthesis ofHMG-CoA reductase are discussed by B. I. Mercer (Prog. Lip. Res.32:357-416 (1993)).

Any compound having activity as a CETP inhibitor can serve as the secondcompound in the combination therapy aspect of the instant invention.

The term CETP inhibitor refers to compounds that inhibit the cholesterylester transfer protein (CETP) mediated transport of various cholesterylesters and triglycerides from HDL to LDL and VLDL. A variety of thesecompounds are described and referenced below; however, other CETPinhibitors will be known to those skilled in the art. U.S. Pat. No.5,512,548 discloses certain polypeptide derivatives having activity asCETP inhibitors, while certain CETP-inhibitory rosenonolactonederivatives and phosphate-containing analogs of cholesteryl ester aredisclosed in J. Antibiot. 49(8):815-816 (1996), and Bioorg. Med. Chem.Lett. 6:1951-1954 (1996), respectively.

Any ACAT inhibitor can serve as an additional compound in thecombination therapy aspect of this invention. The term ACAT inhibitorrefers to a compound that inhibits the intracellular esteriflcation ofdietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase.Such inhibition may be determined readily by one of skill in the artaccording to standard assays, such as the method of Heider et al.described in J. Lipid Res., 24:1127 (1983). A variety of these compoundsare described and referenced below; however, other ACAT inhibitors willbe known to those skilled in the art. U.S. Pat. No. 5,510,379 disclosescertain carboxysulfonates, while WO 96/26948 and WO 96/10559 bothdisclose urea derivatives having ACAT inhibitory activity.

Any compound having activity as a squalene synthetase inhibitor canserve as an additional compound in the combination therapy aspect of theinstant invention. The term squalene synthetase inhibitor refers tocompounds that inhibit the condensation of two molecules offarnesylpyrophosphate to form squalene, a reaction that is catalyzed bythe enzyme squalene synthetase. Such inhibition is readily determined bythose skilled in the art according to standard methodology (Meth.Enzymology 15:393-454 (1969); and Meth. Enzymology, 110:359-373 (1985);and references cited therein). A summary of squalene synthetaseinhibitors has been complied in Curr. Op. Ylter. Patents, 861-4, (1993).EP 0 567 026 A1 discloses certain 4,1-benzoxazepine derivatives assqualene synthetase inhibitors and their use in the treatment ofhypercholesterolemia and as fungicides. EP 0 645 378 A1 disclosescertain seven- or eight-membered heterocycles as squalene synthetaseinhibitors and their use in the treatment and preventionhypercholesterolemia and fulngal infections. EP 0 645 377 A1 disclosescertain benzoxazepine derivatives as squalene synthetase inhibitorsuseful for the treatment of hypercholesterolemia or coronary sclerosis.EP 0 611 749 A1 discloses certain substituted amic acid derivativesuseful for the treatment of arteriosclerosis. EP 0 705 607 A2 disclosescertain condensed seven- or eight-membered heterocyclic compounds usefulas antihypertriglycerideniic agents. WO 96/09827 discloses certaincombinations of cholesterol absorption inhibitors and cholesterolbiosynthesis inhibitors including benzoxazepine derivatives andbenzothiazepine derivatives. EP 0 701 725 A1 discloses a process forpreparing certain optically-active compounds, including benzoxazepinederivatives, having plasma cholesterol and triglyceride loweringactivities.

Other compounds that are currently or previously marketed forhyperlipidemia, including hypercholesterolemia, and which are intendedto help prevent or treat atherosclerosis, include bile acidsequestrants, such as colestipol HCl and cholestyramine; and fibric acidderivatives, such as clofibrate, fenofibrate, and gemfibrozil. Thesecompounds can also be used in combination with a compound of the presentinvention.

It is also contemplated that the compounds of the present invention beadministered with a lipase inhibitor and/or a glucosidase inhibitor,which are typically used in the treatment of conditions resulting fromthe presence of excess triglycerides, free fatty acids, cholesterol,cholesterol esters or glucose including, inter alia, obesity,hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like.

In a combination with a compound of the present invention, any lipaseinhibitor or glucosidase inhibitor may be employed. In one aspect lipaseinhibitors comprise gastric or pancreatic lipase inhibitors. In afurther aspect glucosidase inhibitors comprise amylase inhibitors.Examples of glucosidase inhibitors are those inhibitors selected fromthe group consisting of acarbose, adiposine, voglibose, miglitol,emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q andsalbostatin. Examples of amylase inhibitors include tendamistat and thevarious cyclic peptides related thereto disclosed in U.S. Pat. No.4,451,455, AI-3688 and the various cyclic polypeptides related theretodisclosed in U.S. Pat. No. 4,623,714, and trestatin, consisting of amixture of trestatin A, trestatin B and trestatin C and the varioustrehalose-containing aminosugars related thereto disclosed in U.S. Pat.No. 4,273,765.

A lipase inhibitor is a compound that inhibits the metabolic cleavage ofdietary triglycerides into free fatty acids and monoglycerides. Undernormal physiological conditions, lipolysis occurs via a two-step processthat involves acylation of an activated serine moiety of the lipaseenzyme. This leads to the production of a fatty acid-lipase hemiacetalintermediate, which is then cleaved to release a diglyceride. Followingfurther deacylation, the lipase-fatty acid intermediate is cleaved,resulting in free lipase, a monoglyceride and a fatty acid. Theresultant free fatty acids and monoglycerides are incorporated into bileacid phospholipid micelles, which are subsequently absorbed at the levelof the brush border of the small intestine. The micelles eventuallyenter the peripheral circulation as chylomicrons. Accordingly,compounds, including lipase inhibitors that selectively limit or inhibitthe absorption of ingested fat precursors are useful in the treatment ofconditions including obesity, hyperlipidemia, hyperlipoproteinemia,Syndrome X, and the like.

Pancreatic lipase mediates the metabolic cleavage of fatty acids fromtriglycerides at the 1- and 3-carbon positions. The primary site of themetabolism of ingested fats is in the duodenum and proximal jejunum bypancreatic lipase, which is usually secreted in vast excess of theamounts necessary for the breakdown of fats in the upper smallintestine. Because pancreatic lipase is the primary enzyme required forthe absorption of dietary triglycerides, inhibitors have utility in thetreatment of obesity and the other related conditions.

Gastric lipase is an immunologically distinct lipase that is responsiblefor approximately 10 to 40% of the digestion of dietary fats. Gastriclipase is secreted in response to mechanical stimulation, ingestion offood, the presence of a fatty meal or by sympathetic agents. Gastriclipolysis of ingested fats is of physiological importance in theprovision of fatty acids needed to trigger pancreatic lipase activity inthe intestine and is also of importance for fat absorption in a varietyof physiological and pathological conditions associated with pancreaticinsufficiency. See, for example, Abrams et al., Gastroenterology 92:125(1987).

A variety of lipase inhibitors are known to one of ordinary skill in theart. However, in the practice of the methods, pharmaceuticalcompositions, and kits of the instant invention, generally lipaseinhibitors are those inhibitors that are selected from the groupconsisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386,WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A,ebelactone B and RHC 80267.

The pancreatic lipase inhibitors lipstatin, 2S, 3S, SS,7Z,1OZ)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,1(t-hexadecanoic acid lactone, and tetrahydrolipostatin (orlistat), 2S,3S,55)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoicacid lactone, and the variously substituted N-formylleucine derivativesand stereoisomers thereof, are disclosed in U.S. Pat. No. 4,598,089.

The pancreatic lipase inhibitor FL-386,1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]-ethanone, andthe variously substituted sulfonate derivatives related thereto, aredisclosed in U.S. Pat. No. 4,452,813.

The pancreatic lipase inhibitor WAY-121898,4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the variouscarbamate esters and pharmaceutically acceptable salts related thereto,are disclosed in U.S. Pat. Nos. 5,512,565; 5,391,571 and 5,602,151.

The lipase inhibitor Bay-N-3176,N-3-trifluoromethylphenyl-N′-3-chloro-4-trifluoromethylphenylurea, andthe various urea derivatives related thereto, are disclosed in U.S. Pat.No. 4,405,644.

The pancreatic lipase inhibitor valilactone, and a process for thepreparation thereof by the microbial cultivation of Aetinomycetes strainMG147-CF2, are disclosed in Kitahara, et al., J. Antibiotics40(11):1647-50 (1987).

The lipase inhibitor esteracin, and certain processes for thepreparation thereof by the microbial cultivation of Streptomyces strainATCC 31336, are disclosed in U.S. Pat. Nos. 4,189,438 and 4,242,453.

The pancreatic lipase inhibitors ebelactone A and ebelactone B, and aprocess for the preparation thereof by the microbial cultivation ofActinomycetes strain MG7-G1, are disclosed in Umezawa et al., J.Antibiotics 33:1594-1596 (1980). The use of ebelactones A and B in thesuppression of monoglyceride formation is disclosed in Japanese Kokai08-143457, published Jun. 4, 1996.

The lipase inhibitor RHC 80267,cyclo-O,O′-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and thevarious bis(iminocarbonyl)dioximes related thereto may be prepared asdescribed in Petersen et al., Liebig's Annalen, 562:205-29 (1949).

The ability of RHC 80267 to inhibit the activity of myocardiallipoprotein lipase is disclosed in Carroll et al., Lipids 27:305-7(1992) and Chuang et al., J. Mol. Cell. Cardiol. 22:1009-16 (1990).

In another aspect of the present invention, the compounds of Formula Ican be used in combination with an additional anti-obesity agent. Theadditional anti-obesity agent in one aspect is selected from the groupconsisting of a β₃-adrenergic receptor agonist, a cholecystokinin-Aagonist, a monoamine reuptake inhibitor, a synipathomimetic agent, aserotoninergic agent, a dopamine agonist, a melanocyte-stimulatinghormone receptor agonist or mimetic, a melanocyte-stimulating hormonereceptor analog, a cannabinoid receptor antagonist, a melaninconcentrating hormone antagonist, leptin, a leptin analog, a leptinreceptor agonist, a galanin antagonist, a lipase inhibitor, a bombesinagonist, a neuropeptide-Y antagonist, a thyromimetic agent,dehydroepiandrosterone or an analog thereof, a glucocorticoid receptoragonist or antagonist, an orexin receptor antagonist, a urocortinbinding protein antagonist, a glucagon-like peptide-1 receptor agonist,and a ciliary neurotrophic factor.

In an additional aspect the anti-obesity agents comprise those compoundsselected from the group consisting of sibutramine, fenfluramine,dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin,phenylpropanolamine pseudoephedrine,{4-[2-(2-[6-aminopyridin-3-yl]2(R)-hydroxyethylamino)ethoxy]phenyl}aceticacid,{4{2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}benzoicacid, {4-[2-(2{6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl} propionicacid, and{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenoxy}aceticacid.

In one aspect, the thyromimetic compounds present may be administered incombination with pharmaceutical agents useful for the prevention ortreatment of diabetes, including impaired glucose tolerance, insulinresistance, insulin dependent diabetes mellitus (Type I) and non-insulindependent diabetes mellitus (NIDDM or Type II). Also included in theprevention or treatment of diabetes are the diabetic complications, suchas neuropathy, nephropathy, retinopathy or cataracts.

In one aspect the type of diabetes to be treated is non-insulindependent diabetes mellitus, also known as Type II diabetes or NIDDM.

Representative agents that can be used to treat diabetes include insulinand insulin analogs (e.g., LysPro insulin); GLP-1 (7-37)(insulinotropin) and GLP-1 (7-36) —NH₂. Agents that enhance insulinsecretion, e.g., eblorpropamide, glibenclamide, tolbutamide, tolazamide,acetohexamide, glypizide, glimepiride, repaglinide, nateglinide,meglitinide; biguanides: metformin, phenformin, buformin; A2-antagonistsand imidazolines: midaglizole, isaglidole, deriglidole, idazoxan,efaroxan, fluparoxan; other insulin secretagogues linogliride, A-4166;glitazones: ciglitazone, pioglitazone, englitazone, troglitazone,darglitazone, BR:9653; fatty acid oxidation inhibitors: clomoxir,etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate,voglibose, MDL-25,637, camiglibose, MDL-73,945; ˜3-agonists: BRL 35135,BRL 37344, RO 16-8714, ICI D7114, CL 316,243; phosphodiesteraseinhibitors: −386,398; lipid-lowering agents benfluorex; antiobesityagents: fenfiuramine; vanadate and vanadium complexes (e.g.,bis(cysteinamide N-octyl) oxovanadium) and peroxovanadium complexes;amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors;somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox,WAG 994. Also contemplated to be used in combination with a compound ofthe present invention are pramlintide (Symlin™), AC 2993 andnateglinide. Any agent or combination of agents can be administered asdescribed above.

In addition, the compounds of the present invention can be used incombination with one or more aldose reductase inhibitors, DPPIVinhibitor, glycogen phosphorylase inhibitors, sorbitol dehydrogenaseinhibitors, NHE-1 inhibitors and/or glucocorticoid receptor antagonists.

Any compound having activity as a fructose-1,6-bisphosphatase (FBPase)inhibitor can serve as the second compound in the combination therapyaspect of the instant invention (e.g.,2-amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazoles).FBPase is a key regulatory enzyme in gluconeogenesis, the metabolicpathway by which the liver synthesizes glucose from 3-carbon precursors.The term FBPase inhibitor refers to compounds that inhibit FBPase enzymeactivity and thereby block the conversion of fructose-1,6-bisphosphate,the substrate of the enzyme, to fructose 6-phosphate. FBPase inhibitioncan be determined directly at the enzyme level by those skilled in theart according to standard methodology (e.g., Gidh-Jain et al., J. Biol.Chem. 269(44):27732-8 (1994)). Alternatively, FBPase inhibition can beassessed according to standard methodology by measuring the inhibitionof glucose production by isolated hepatocytes or in a perfused liver, orby measuring blood glucose lowering in normal or diabetic animals (e.g.,Vincent et al., Diabetologia 39(10):1148-55 (1996); Vincent et al.,Diabetes 40(10):1259-66 (1991)). In some cases, in vivo metabolicactivation of a compound may be required to generate the FBPaseinhibitor. This class of compounds may be inactive in the enzymeinhibition screen, may or may not be active in hepatocytes, but isactive in vivo as evidenced by glucose lowering in the normal, fastedrat and/or in animal models of diabetes.

A variety of FBPase inhibitors are described and referenced below;however, other FBPase inhibitors will be known to those skilled in theart. Gruber et al. U.S. Pat. No. 5,658,889 described the use ofinhibitors of the AMP site of FBPase to treat diabetes; WO 98/39344 andU.S. Pat. No. 6,284,748 describe purine inhibitors; WO 98/39343 and U.S.Pat. No. 6,110,903 describe benzothiazole inhibitors to treat diabetes;WO 98/39342 and U.S. Pat. No. 6,054,587 describe indole inhibitors totreat diabetes; and WO 00/14095 and U.S. Pat. No. 6,489,476 describeheteroaromatic phosphonate inhibitors to treat diabetes. Other FBPaseinhibitors are described in Wright et al., J. Med. Chem. 45(18):3865-77(2002) and WO 99/47549.

The thyromimetic compounds can also be used in combination withsulfonylureas such as amaryl, alyburide, glucotrol, chlorpropamide,diabinese, tolazamide, tolinase, acetohexamide, glipizide, tolbutamide,orinase, glimepiride, DiaBeta, micronase, glibenclamide, and gliclazide.

The thyromimetic compounds can also be used in combination withantihypertensive agents. Any anti-hypertensive agent can be used as thesecond agent in such combinations. Examples of presently marketedproducts containing antihypertensive agents include calcium channelblockers, such as Cardizem, Adalat, Calan, Cardene, Covera, Dilacor,DynaCirc, Procardia XL, Sular, Tiazac, Vascor, Verelan, Isoptin,Nimotop, Norvase, and Plendil; angiotensin converting enzyme (ACE)inhibitors, such as Accupril, Altace, Captopril, Lotensin, Mavik,Monopril, Prinivil, Univasc, Vasotec and Zestril.

Examples of compounds that may be used in combination with the compoundsof the present invention to prevent or treat osteoporosis include:anti-resorptive agents including progestins, polyphosphonates,bisphosphonate(s), estrogen agonists/antagonists, estrogen,estrogen/progestin combinations, Premarin, estrone, estriol or 17α- or17β-ethynyl estradiol); progestins including algestone acetophenide,altrenogest, amadinone acetate, anagestone acetate, chlormadinoneacetate, cingestol, clogestone acetate, clomegestone acetate,delmadinone acetate, desogestrel, dimethisterone, dydrogesterone,ethynerone, ethynodiol diacetate, etonogestrel, fluorogestone acetate,gestaclone, gestodene, gestonorone caproate, gestrinone,haloprogesterone, hydroxyprogesterone caproate, levonorgestrel,lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrolacetate, methynodiol diacetate, norethindrone, norethindrone acetate,norethynodrel, norgestimate, norgestomet, norgestrel, oxogestonephenpropionate, progesterone, quingestanol acetate, quingestrone, andtigestol; and bone resorption inhibiting polyphosphonates includingpolyphosphonates such as of the type disclosed in U.S. Pat. No.3,683,080, the disclosure of which is incorporated herein by reference.Examples of polyphosphonates include geminal diphosphonates (alsoreferred to as bis-phosphonates), tiludronate disodium, ibandronic acid,alendronate, resindronate zoledronic acid,6-amino-1-hydroxy-hexylidene-bisphosphonic acid and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. Salts,co-crystals and esters of the polyphosphonates are likewise included.Specific examples include ethane-1-hydroxy 1,1-diphosphonic acid,methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid,methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-t-hydroxy-1,1-diphosphonic acid,propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid, N,N-dimethylamino methane diphosphonicacid, N(2-hydroxyethyl)amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1,1-diphosphonic acid, andhexanc-6-amino-1-hydroxy-1,1-diphosphonic acid.

Estrogen agonist/antagonist include3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid, tamoxifen:(ethanamine,2-(−4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl,(Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1))and related compounds which are disclosed in U.S. Pat. No. 4,536,516,the disclosure of which is incorporated herein by reference, 4-hydroxytamoxifen, which is disclosed in U.S. Pat. No. 4,623,660, the disclosureof which is incorporated herein by reference, raloxifene: (methanone,(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)-hydrochloride)which is disclosed in U.S. Pat. No. 4,418,068, the disclosure of whichis incorporated herein by reference, toremifene: (ethanamine,2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl,(Z)-,2-hydroxy-1,2,3-propanetricarboxylate(1:1) which is disclosed in U.S. Pat. No. 4,996,225, the disclosure ofwhich is incorporated herein by reference, centchroman:1-(2-((4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine, which isdisclosed in U.S. Pat. No. 3,822,287, the disclosure of which isincorporated herein by reference, levorneloxifene, idoxifene:(E)-1-(2-(4-(1-(4-iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone,which is disclosed in U.S. Pat. No. 4,839,155, the disclosure of whichis incorporated herein by reference,2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olwhich is disclosed in U.S. Pat. No. 5,488,058, the disclosure of whichis incorporated herein by reference,6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol,which is disclosed in U.S. Pat. No. 5,484,795, the disclosure of whichis incorporated herein by reference,(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)-methanonewhich is disclosed, along with methods of preparation, in PCTpublication no. WO 95/10513 assigned to Pfizer Inc, TSE-424(Wyeth-Ayerst Laboratories) and arazoxifene,cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-tetrahydro-naphthalene-2-ol;(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol(also known as lasofoxifene);cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-(6′-pyrrolodinoethoxy-3′-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline,2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

Other anti-osteoporosis agents, which can be used as the second agent incombination with a compound of the present invention, include, forexample, the following: parathyroid hormone (PTH) (a bone anabolicagent); parathyroid hormone PTH) secretagogues (see, e.g., U.S. Pat. No.6,132,774), particularly calcium receptor antagonists; calcitonin; andvitamin D and vitamin D analogs. Further anti-osteoporosis agentsincludes a selective androgen receptor modulator (SARM). Examples ofsuitable SARMs include compounds such as cyproterone acetate,chlormadinone, flutamide, hydroxyflutamide, bicalutamide, nilutamide,spironolactone, 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinederivatives, 1,2-dihydropyridino[5,6-g]quinoline derivatives andpiperidino[3,2-g]quinolinone derivatives. Other examples includecypterone, also known as(1b,2b)-6-chloro-1,2-dihydro-17-hydroxy-3′-H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dioneis disclosed in U.S. Pat. No. 3,234,093. Chlormadinone, also known as17-(acetyloxy)-6-chloropregna-4,6-diene-3,20-dione, in its acetate form,acts as an anti-androgen and is disclosed in U.S. Pat. No. 3,485,852.Nilutamide, also known as5,5-dimethyl-3-[4-nito-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedioneand by the trade name Nilandron® is disclosed in U.S. Pat. No.4,097,578. Flutamide, also known as2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide and the tradename Eulexin® is disclosed in U.S. Pat. No. 3,847,988. Bicalutamide,also known as4′-cyano-a′,a′,a′-trifluoro-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidideand the trade name Casodex® is disclosed in EP-100172. The enantiomersof biclutamide are discussed by Tucker et al., J. Med. Chem. 31:885-887(1988). Hydroxyflutamide, a known androgen receptor antagonist in mosttissues, has been suggested to function as a SARM for effects on IL-6production by osteoblasts as disclosed in Hofbauer et al., J. BoneMiner. Res. 14:1330-1337 (1999). Additional SARMs have been disclosed inU.S. Pat. No. 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO02/00617, WO 02/16310, U.S. Patent Application Publication No. US2002/0099096, U.S. Patent Application Publication No. US 2003/0022868,WO 03/011302 and WO 03/011824. All of the above references are herebyincorporated by reference herein.

Formulations

Unit dose amounts and dose scheduling for the pharmaceuticalcompositions of the present invention can be determined using methodswell known in the art. In one aspect, the compounds of the invention areadministered orally in a total daily dose of about 0.375 μg/kg/day toabout 3.75 mg/kg/day. In another aspect the total daily dose is fromabout 3.75 μg/kg/day to about 0.375 mg/kg/day. In another aspect thetotal daily dose is from about 3.75 μg/kg/day to about 37.5 μg/kg/day.In another aspect the total daily dose is from about 3.75 μg/kg/day toabout 60 μg/kg/day. In a further aspect the dose range is from 30μg/kg/day to 3.0 mg/kg/day. In one aspect, the compounds of theinvention are administered orally in a unit dose of about 0.375 μg/kg toabout 3.75 mg/kg. In another aspect the unit dose is from about 3.75μg/kg to about 0.375 mg/kg. In another aspect the unit dose is fromabout 3.75 μg/kg to about 37.5 μg/kg. In another aspect the unit dose isfrom about 3.75 μg/kg to about 60 μg/kg. In one aspect, the compounds ofthe invention are administered orally in a unit dose of about 0.188μg/kg to about 1.88 mg/kg. In another aspect the unit dose is from about1.88 μg/kg to about 0.188 mg/kg. In another aspect the unit dose is fromabout 1.88 μg/kg to about 18.8 μg/kg. In another aspect the unit dose isfrom about 1.88 μg/kg to about 30 μg/kg. In one aspect, the compounds ofthe invention are administered orally in a unit dose of about 0.125μg/kg to about 1.25 mg/kg. In another aspect the unit dose is from about1.25 μg/kg to about 0.125 mg/kg. In another aspect the unit dose is fromabout 1.25 μg/kg to about 12.5 μg/kg. In another aspect the unit dose isfrom about 1.25 μg/kg to about 20 μg/kg. In one embodiment the unit doseis administered once a day. In another embodiment the unit dose isadministered twice a day. In another embodiment the unit dose isadministered three times a day. In another embodiment the unit dose isadministered four times a day.

Dose refers to the equivalent of the free acid. The use ofcontrolled-release preparations to control the rate of release of theactive ingredient may be preferred. The daily dose may be administeredin multiple divided doses over the period of a day. Doses and dosingschedules may be adjusted to the form of the drug or form of deliveryused. For example, different dosages and scheduling of doses may be usedwhen the form of the drug is in a controlled release form or intravenousdelivery is used with a liquid form.

Compounds of this invention when used in combination with othercompounds or agents may be administered as a daily dose or anappropriate fraction of the daily dose (e.g., bid). Administration ofcompounds of this invention may occur at or near the time in which theother compound or agent is administered or at a different time. Whencompounds of this invention are used in combination with other compoundsor agents, the other compound or agent (e.g., atorvastatin) may beadministered at the approved dose or a lower dose.

For the purposes of this invention, the compounds may be administered bya variety of means including orally, parenterally, by inhalationincluding but not limited to nasal spray, topically, implantables orrectally in formulations containing pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereincludes subcutaneous, intravenous, intramuscular, and intra-arterialinjections with a variety of infusion techniques. Intra-arterial andintravenous injection as used herein includes administration throughcatheters. Oral administration is generally preferred.

Pharmaceutical compositions containing the active ingredient may be inany form suitable for the intended method of administration. When usedfor oral use for example, tablets, pellets, troches, lozenges, aqueousor oil suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, syrups or elixirs may be prepared. Compositions intendedfor oral use may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets and pellets containing the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipient which are suitable for manufacture of tablets are acceptable.These excipients may be, for example, inert diluents, such as calcium orsodium carbonate, lactose, calcium or sodium phosphate; granulating anddisintegrating agents, such as maize starch, or alginic acid; bindingagents, such as starch, gelatin or acacia; and lubricating agents, suchas magnesium stearate, stearic acid or talc. Tablets and pellets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders, pellets, and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, such as olive oil orarachis oil, a mineral oil, such as liquid paraffin, or a mixture ofthese. Suitable emulsifying agents include naturally-occurring gums,such as gum acacia and gum tragacanth, naturally occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids and hexitol anhydrides, such as sorbitan monooleate, andcondensation products of these partial esters with ethylene oxide, suchas polyoxyethylene sorbitan monooleate. The emulsion may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

In another aspect the pharmaceutical compositions may be in the form ofa sterile injectable preparation, such as a sterile injectable aqueousor oleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain 0.2 to 2000 μmol (approximately 0.1 to 1000 mg) of activematerial compounded with an appropriate and convenient amount of carriermaterial which may vary from about 5 to about 99.9% of the totalcompositions. It is preferred that the pharmaceutical composition beprepared which provides easily measurable amounts for administration.For example, an aqueous solution intended for intravenous infusionshould contain from about 0.05 to about 500 umol (approximately 0.025 to250 mg) of the active ingredient per milliliter of solution in orderthat infusion of a suitable volume at a rate of about 30 mL/h can occur.

As noted above, formulations suitable for oral administration may bepresented as discrete units such as capsules, cachets, pellets, ortablets each containing a predetermined amount of the active ingredient;as a powder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. Tablets mayoptionally be provided with an enteric coating, to provide release inparts of the gut other than the stomach. This is particularlyadvantageous with the compounds of the present invention when suchcompounds are susceptible to acid hydrolysis.

Pharmaceutical compositions comprising the compounds of the presentinvention can be administered by controlled- or delayed-release means.Controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledrelease counterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to treat or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include: 1) extended activity of the drug; 2) reduceddosage frequency; 3) increased patient compliance; 4) usage of lesstotal drug; 5) reduction in local or systemic side effects; 6)minimization of drug accumulation; 7) reduction in blood levelfluctuations; 8) improvement in efficacy of treatment; 9) reduction ofpotentiation or loss of drug activity; and 10) improvement in speed ofcontrol of diseases or conditions. (Kim, Controlled Release Dosage FormDesign, 2 Technomic Publishing, Lancaster, Pa.: 2000).

Conventional dosage forms generally provide rapid or immediate drugrelease from the formulation. Depending on the pharmacology andpharmacokinetics of the drug, use of conventional dosage forms can leadto wide fluctuations in the concentrations of the drug in a patient'sblood and other tissues. These fluctuations can impact a number ofparameters, such as dose frequency, onset of action, duration ofefficacy, maintenance of therapeutic blood levels, toxicity, sideeffects, and the like. Advantageously, controlled-release formulationscan be used to control a drug's onset of action, duration of action,plasma levels within the therapeutic window, and peak blood levels. Inparticular, controlled- or extended-release dosage forms or formulationscan be used to ensure that the maximum effectiveness of a drug isachieved while minimizing potential adverse effects and safety concerns,which can occur both from under dosing a drug (i.e., going below theminimum therapeutic levels) as well as exceeding the toxicity level forthe drug.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, ionic strength, osmotic pressure, temperature, enzymes, water, andother physiological conditions or compounds.

A variety of known controlled- or extended-release dosage forms,formulations, and devices can be adapted for use with the compositionsof the invention. Examples include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,733,566; and 6,365,185 B1; each of which isincorporated herein by reference. These dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydroxypropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems (such as OROS®(Alza Corporation, Mountain View, Calif. USA)), multilayer coatings,microparticles, liposomes, or microspheres or a combination thereof toprovide the desired release profile in varying proportions.Additionally, ion exchange materials can be used to prepare immobilizedforms of compositions of the invention and thus effect controlleddelivery of the drug. Examples of specific anion exchangers include, butare not limited to, DUOLITE A568 and DUOLITE AP143 (Rohm & Haas, SpringHouse, Pa. USA).

One embodiment of the invention encompasses a unit dosage form whichcomprises a compound of the present invention or a pharmaceuticallyacceptable salt, or a polymorph, solvate, hydrate, dehydrate,co-crystal, anhydrous, or amorphous form thereof, and one or morepharmaceutically acceptable excipients or diluents, wherein thepharmaceutical composition or dosage form is formulated forcontrolled-release. Specific dosage forms utilize an osmotic drugdelivery system.

A particular and well-known osmotic drug delivery system is referred toas OROS (Alza Corporation, Mountain View, Calif. USA). This technologycan readily be adapted for the delivery of compounds and compositions ofthe invention. Various aspects of the technology are disclosed in U.S.Pat. Nos. 6,375,978 B1; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2;6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; and 6,132,420;each of which is incorporated herein by reference. Specific adaptationsof OROS that can be used to administer compounds and compositions of theinvention include, but are not limited to, the OROS Push-Pull, DelayedPush-Pull, Multi-Layer Push-Pull, and Push-Stick Systems, all of whichare well known. Additional OROS systems that can be used for thecontrolled oral delivery of compounds and compositions of the inventioninclude OROS-CT and L-OROS. Id.; see also, Delivery Times, vol. 1, issueII (Alza Corporation).

Conventional OROS oral dosage forms are made by compressing a drugpowder (e.g., a T3 mimetic composition of the present invention) into ahard tablet, coating the tablet with cellulose derivatives to form asemi-permeable membrane, and then drilling an orifice in the coating(e.g., with a laser). (Kim, Controlled Release Dosage Form Design,231-238 Technomic Publishing, Lancaster, Pa. 2000). The advantage ofsuch dosage forms is that the delivery rate of the drug is notinfluenced by physiological or experimental conditions. Even a drug witha pH-dependent solubility can be delivered at a constant rate regardlessof the pH of the delivery medium. But because these advantages areprovided by a build-up of osmotic pressure within the dosage form afteradministration, conventional OROS drug delivery systems cannot be usedto effectively deliver drugs with low water solubility.

A specific dosage form of the invention comprises: a wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a dry orsubstantially dry state drug layer located within the cavity adjacent tothe exit orifice and in direct or indirect contacting relationship withthe expandable layer; and a flow-promoting layer interposed between theinner surface of the wall and at least the external surface of the druglayer located within the cavity, wherein the drug layer comprises acompound of the present invention, including a polymorph, solvate,hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.See U.S. Pat. No. 6,368,626, the entirety of which is incorporatedherein by reference.

Another specific dosage form of the invention comprises: a wall defininga cavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a drug layerlocated within the cavity adjacent the exit orifice and in direct orindirect contacting relationship with the expandable layer; the druglayer comprising a liquid, active agent formulation absorbed in porousparticles, the porous particles being adapted to resist compactionforces sufficient to form a compacted drug layer without significantexudation of the liquid, active agent formulation, the dosage formoptionally having a placebo layer between the exit orifice and the druglayer, wherein the active agent formulation comprises a compound of thepresent invention, including a polymorph, solvate, hydrate, dehydrate,co-crystal, anhydrous, or amorphous form thereof. See U.S. Pat. No.6,342,249, the entirety of which is incorporated herein by reference.

Transdermal Delivery System: The controlled release formulations of thepresent invention may be formulated as a transdermal delivery system,such as transdermal patches. In certain embodiments of the presentinvention, a transdermal patch comprises a compound of the presentinvention contained in a reservoir or a matrix, and an adhesive whichallows the transdermal device to adhere to the skin, allowing thepassage of the active agent from the transdermal device through the skinof the patient. Once the compound has penetrated the skin layer, thedrug is absorbed into the blood stream where it exerts desiredpharmaceutical effects. The transdermal patch releases the compound ofthe present invention in a controlled-release manner, such that theblood levels of the a compound of the present invention is maintained ata therapeutically effective level through out the dosing period, and theblood levels of the a compound of the present invention is maintained ata concentration that is sufficient to reduce side effects associatedwith immediate release dosage forms but not sufficient to negate thetherapeutic effectiveness of the compound.

Transdermal refers to the delivery of a compound by passage through theskin or mucosal tissue and into the blood stream. There are four maintypes of transdermal patches listed below.

-   -   1. Single-layer Drug-in-Adhesive: The adhesive layer of this        system also contains the drug. In this type of patch the        adhesive layer not only serves to adhere the various layers        together, along with the entire system to the skin, but is also        responsible for the releasing of the drug. The adhesive layer is        surrounded by a temporary liner and a backing.    -   2. Multi-layer Drug-in-Adhesive: The multi-layer drug-in        adhesive patch is similar to the single-layer system in that        both adhesive layers are also responsible for the releasing of        the drug. The multi-layer system is different however that it        adds another layer of drug-in-adhesive, usually separated by a        membrane (but not in all cases). This patch also has a temporary        liner-layer and a permanent backing.    -   3. Reservoir: Unlike the Single-layer and Multi-layer        Drug-in-adhesive systems the reservoir transdermal system has a        separate drug layer. The drug layer is a liquid compartment        containing a drug solution or suspension separated by the        adhesive layer. This patch is also backed by the backing layer.    -   4. Matrix: The Matrix system has a drug layer of a semisolid        matrix containing a drug solution or suspension. The adhesive        layer in this patch surrounds the drug layer partially        overlaying it.        Other modes of transdermal delivery are known in the art and are        included in the present invention.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin, or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containantioxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

In one aspect the unit dosage formulations are those containing a dailydose or unit, daily sub-dose, or an appropriate fraction thereof, of adrug.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed; the age, body weight,general health, sex and diet of the individual being treated; the timeand route of administration; the rate of excretion; other drugs whichhave previously been administered; and the severity of the particulardisease undergoing therapy, as is well understood by those skilled inthe art.

Synthesis of Compounds Useful in the Present Invention

The compounds in this invention may be prepared by the processesdescribed in relevant published literature procedures that are used bythose skilled in the art. Carboxylic acid-containing compounds andrelated compounds may be prepared as disclosed in U.S. Pat. Nos.6,465,687 and 6,747,048, U.S. Published Application Nos. 2004/0097589,2004/0116387, 2004/0220147, and 2005/0004184, WO 00/07972, WO 01/36365,and WO 2004/007430, each herein incorporated by reference. In addition,the following Schemes may be used to prepare phosphorus-containingcompounds. It should be understood that the following Schemes areprovided solely for the purpose of illustration and do not limit theinvention which is defined by the claims. In all applicable structurescontained in the Schemes described in this invention, PG refers to aprotecting group and FG refers to a functional group that can betransformed into T. Protection and deprotection in the Schemes may becarried out according to the procedures generally known in the art(e.g., “Protecting Groups in Organic Synthesis,” 3rd Edition, Wiley,1999).

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The processes for preparation can utilize racemates, enantiomers ordiastereomers as starting materials. When enantiomeric or diastereomericproducts are prepared, they can be separated by conventional methods,for example, chromatographic or fractional crystallization.

Preparation of a Phosphonate Prodrug

Prodrugs can be introduced at different stages of the synthesis. Mostoften these prodrugs are made from the phosphonic acids because of theirlability.

Phosphonic acids of Formula I-VII can be alkylated with electrophilessuch as alkyl halides and alkyl sulfonates under nucleophilicsubstitution conditions to give phosphonate esters. For example,compounds of Formula I-VII wherein YR¹¹ is an acyloxyalkyl group can beprepared by direct alkylation of compounds of Formula I-VII with anappropriate acyloxyalkyl halide (e.g., Cl, Br, I; Phosphorus Sulfur54:143 (1990); Synthesis 62 (1988)) in the presence of a suitable base(e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents suchas DMF (J. Med. Chem. 37:1875 (1994)). The carboxylate component ofthese acyloxyalkyl halides includes but is not limited to acetate,propionate, isobutyrate, pivalate, benzoate, carbonate and othercarboxylates.

Dimethylformamide dialkyl acetals can also be used for the alkylation ofphosphonic acids (Collect. Czech Chem. Commu. 59:1853 (1994)). Compoundsof Formula I-VII wherein YR¹¹ is a cyclic carbonate, a lactone or aphthalidyl group can also be synthesized by direct alkylation of thefree phosphonic acids with appropriate halides in the presence of asuitable base such as NaH or diisopropylethylamine (J. Med. Chem.38:1372 (1995); J. Med. Chem. 37:1857 (1994); J. Pharm. Sci. 76:180(1987)).

Alternatively, these phosphonate prodrugs can be synthesized by thereactions of the corresponding dichlorophosphonates and an alcohol(Collect Czech Chem. Commun. 59:1853 (1994)). For example, adichlorophosphonate is reacted with substituted phenols and arylalkylalcohols in the presence of a base such as pyridine or TEA to give thecompounds of Formula I-VII wherein YR¹¹ is an aryl group (J. Med. Chem.39:4109 (1996); J. Med. Chem. 38:1372 (1995); J. Med. Chem. 37:498(1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans. 1 38:2345(1992)). The disulfide-containing prodrugs (Antiviral Res. 22:155(1993)) can be prepared from a dichlorophosphonate and2-hydroxyethyldisulfide under standard conditions. Dichlorophosphonatesare also useful for the preparation of various phosphonamides asprodrugs. For example, treatment of a dichlorophosphonate with ammoniagives both a monophosphonamide and a diphosphonamide; treatment of adichlorophosphonate with 1-amino-3-propanol gives a cyclic1,3-propylphosplionamide; treatment of a chlorophosphonate monophenylester with an amino acid ester in the presence of a suitable base givesa substituted monophenyl monophosphonamidate.

Such reactive dichlorophosphonates can be generated from thecorresponding phosphonic acids with a chlorinating agent (e.g., thionylchloride, J. Med. Chem. 1857 (1994); oxalyl chloride, Tetrahedron Lett.31:3261 (1990); phosphorous pentachloride, Synthesis 490 (1974)).Alternatively, a dichlorophosphonate can be generated from itscorresponding disilyl phosphonate esters (Synth. Commu. 17:1071 (1987))or dialkyl phosphonate esters (Tetrahedron Lett. 24:4405 (1983); Bull.Soc. Chim. 130:485 (1993)).

It is envisioned that compounds of Formula I-VII can be mixedphosphonate ester (e.g., phenyl and benzyl esters, or phenyl andacyloxyalkyl esters) including the chemically combined mixed esters suchas phenyl and benzyl combined prodrugs reported in Bioorg. Med. Chem.Lett. 7:99 (1997).

Dichlorophosphonates are also useful for the preparation of variousphosphonamides as prodrugs. For example, treatment of adichlorophosphonate with an amine (e.g. an amino acid alkyl ester suchas L-alanine ethyl ester) in the presence of a suitable base (e.g.triethylamine, pyridine, etc.) gives the corresponding bisphosphonamide;treatment of a dichlorophosphonate with 1-amino-3-propanol gives acyclic 1,3-propylphosphonamide; treatment of a chlorophosphonatemonophenyl ester with an amino acid ester in the presence of a suitablebase gives a substituted monophenyl monophosphonamidate. Directcouplings of a phosphonic acid with an amine (e.g. an amino acid alkylester such as L-alanine ethyl ester) are also reported to give thecorresponding bisamidates under Mukaiyama conditions (J. Am. Chem. Soc.,94:8528 (1972)).

The SATE (S-acetyl thioethyl) prodrugs can be synthesized by thecoupling reaction of the phosphonic acids of Formula I-VII andS-acyl-2-thioethanol in the presence of DCC, EDCI or PyBOP (J. Med.Chem. 39:1981 (1996)).

Cyclic phosphonate esters of substituted 1,3-propane diols can besynthesized by either reactions of the corresponding dichlorophosphonatewith a substituted 1,3-propanediol or coupling reactions using suitablecoupling reagents (e.g., DCC, EDCI, PyBOP; Synthesis 62 (1988)). Thereactive dichlorophosphonate intermediates can be prepared from thecorresponding acids and chlorinating agents such as thionyl chloride (J.Med. Chem. 1857 (1994)), oxalyl chloride (Tetrahedron Lett. 31:3261(1990)) and phosphorus pentachloride (Synthesis 490 (1974)).Alternatively, these dichlorophosphonates can also be generated fromdisilyl esters (Synth. Commun. 17:1071 (1987)) and dialkyl esters(Tetrahedron Lett. 24:4405 (1983); Bull. Soc. Chim. Fr., 130:485(1993)).

Alternatively, these cyclic phosphonate esters of substituted1,3-propane diols are prepared from phosphonic acids by coupling withdiols under Mitsunobu reaction conditions (Synthesis 1 (1981); J Org.Chem. 52:6331 (1992)), and other acid coupling reagents including, butnot limited to, carbodiimides (Collect. Czech. Chem. Commun. 59:1853(1994); Bioorg. Med. Chem. Lett. 2:145 (1992); Tetrahedron Lett. 29:1189(1988)), and benzotriazolyloxytris-(dimethylamino) phosphonium salts(Tetrahedron Lett. 34:6743 (1993)).

Phosphonic acids also undergo cyclic prodrug formation with cyclicacetals or cyclic ortho esters of substituted propane-1,3-diols toprovide prodrugs as in the case of carboxylic acid esters (Helv. Chim.Acta. 48:1746 (1965)). Alternatively, more reactive cyclic sulfites orsulfates are also suitable coupling precursors to react with phosphonicacid salts. These precursors can be made from the corresponding diols asdescribed in the literature.

Alternatively, cyclic phosphonate esters of substituted 1,3-propanediols can be synthesized by tranis esterification reaction withsubstituted 1,3-propane diol under suitable conditions. Mixed anhydridesof parent phosphonic acids generated in situ under appropriateconditions react with diols to give prodrugs as in the case ofcarboxylic acid esters (Bull. Chem. Soc. Jpn. 52:1989 (1979)). Arylesters of phosphonates are also known to undergo transesterificationwith alkoxy intermediates (Tetrahedron Lett. 38:2597 (1997); Synthesis968 (1993)).

One aspect of the present invention provides methods to synthesize andisolate single isomers of prodrugs of phosphonic acids of Formula I-VII.Because phosphorus is a stereogenic atom, formation of a prodrug with aracemic substituted-1,3-propane-diol will produce a mixture of isomers.For example, formation of a prodrug with a racemic1-(V)-substituted-1,3-propane diol gives a racemic mixture ofcis-prodrugs and a racemic mixture of trans-prodrugs. In an otheraspect, the use of the enantioenriched substituted-1,3-propane diol withthe R-configuration gives enantioemiched R-cis- and R-trans-prodrugs.These compounds can be separated by a combination of columnchromatography and/or fractional crystallization.

A. Deprotection of A Phosphonate Ester

Compounds of Formula II-VII wherein X is —PO₃H₂ may be prepared fromphosphonate esters using the known cleavage methods. Silyl halides aregenerally used to cleave various phosphonate esters and give the desiredphosphonic acid upon mild hydrolysis of the resulting silyl phosphonateesters. When needed, acid scavengers (for example, HANDS) can be usedfor the acid sensitive compounds. Such silyl halides include TMSC1 (J.Org. Chem. 28:2975 (1963)), TMSBr (Tetrahedron Lett. 155 (1977)) andTMSI (J. Chem. Soc., Chem. Commu. 870 (1978)). Alternatively,phosphonate esters can be cleaved under strong acid conditions(Tetrahedron Lett. 33:4137 (1992); Synthesis-Stuttgart 10:955 (1993)).Those phosphonate esters can also be cleaved via dichlorophosphonatesprepared by treating the phosphonate esters with halogenating agentssuch as PCl₅, SOCl₂ and BF₃ (J. Chem. Soc. 238 (1961)) followed byaqueous hydrolysis to give the phosphonic acids. Aryl and benzylphosphonate esters can be cleaved under hydrogenolysis conditions(Synthesis 412 (1982); J. Med. Chem. 281208 (1985)) or metal reductionconditions (J. Chem. Soc. 99:5118 (1977)). Electrochemical (J. Org.Chem. 44:4508 (1979)) and pyrolysis (Synth. Commu. 10:299 (1980))conditions have been used to cleave various phosphonate esters.

Introduction of A Phosphonate Group

The introduction of a phosphonate group can generally be accomplishedaccording to known methods. Compounds of Formula I, II, II, V, VI, andVII wherein T is —O(CR^(b) ₂)(CR^(a) ₂)_(n)—, —S(CR^(b) ₂)(CR^(a)₂)_(n)— or —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)— may be prepared bycoupling a phenol, thiophenol, or aniline with a phosphonate estercomponent such as I(CR^(b) ₂)(CR^(a) ₂)_(n)P(O)(OEt)₂, TsO(CR^(b)₂)(CR^(a) ₂)_(n)P(O)(OEt)₂, or TfO(CR^(b) ₂)(CR^(a) ₂)_(n)P(O)(OEt)₂ inthe presence of a base such as NaH, K₂CO₃, KO-t-Bu or TEA (TetrahedronLett. 27:1477 (1986); J. Chem. Soc. Perkin Tran 1 1987 (1994)) asdescribed in Scheme 1. Following the procedures described as above,deprotection of the phosphonate ester 2 gives the desired phosphonicacid 3.

Compounds of Formula I, II, III, V, VI, and VII wherein T is—N(R^(b))C(O)(CR^(a) ₂)_(n)— can be prepared by coupling an aniline 1(M=NH) with a carboxylic acid containing a phosphonate moiety(EtO)₂P(O)(CR^(a) ₂)₁₋₂CO₂H in the presence of DCC or EDC according tothe known methods (for example, J. Org. Chem. 42:2019 (1977)) orconverting an aniline 1 (M=NH) to an isocyanate with diphosgene followedby reacting with P(OEt)₃ (J. Org. Chem. 1661 (1956); Tetrahedron Lett.37:5861 (1996)). Deprotection of the phosphonate ester 2 as describedabove leads to the phosphonic acid 3.

For compounds of Formula I, II, III, V, VI, and VII wherein T is—(CR^(a) ₂)_(k)—, the phosphonate group can be introduced by a number ofknown methods. For example, the coupling reaction of a phenyl bromide(J. Org. Chem. 64:120 (1999)), iodide (Phosphorus Sulfur 130:59 (1997))or triflate (J. Org. Chem. 66:348 (2001)) with diethyl phosphonate inthe presence of a Pd catalyst is widely used within the art (when k is0). Other methods such as Michaelis-Arbuzov reaction (Chem. Rev. 81:415(1981)) can also be an efficient way to introduce the phosphonate groupby coupling a benzyl or arylalkyl halide with triethyl phosphonate (whenm is 1-3).

For compounds of Formula I, II, III, V, VI, and VII wherein T is—(CR^(a) ₂), —CR^(b)═CR^(b)—, the phosphonate group can be introduced bycoupling an aldehyde and tetraethyl methylenediphosphonate in thepresence of a base such as NaH, NaOH or KO-t-Bu (Tetrahedron Lett.29:3007 (1988)). For compounds of Formula I, II, III, V, VI, and VIIwherein T is —CR^(b)═CR^(b)— (CR^(a) ₂)_(n)— or—(CR₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, the phosphonate group can beintroduced by Michaelis-Arbuzov reaction of the corresponding olefinichalide with triethyl phosphite.

For compounds of Formula II, III, V, VI, and VII wherein T is —(CR^(a)₂)_(m)(CO)—, the phosphonate group can be introduced by reacting diethylphosphite with an acid chloride (J. Org, Chem. 29:3862 (1964);Tetrahedron 54:12233 (1998)) or an aldehyde followed by oxidation(Tetrahedron 52:9963 (1996)). Also, this type of compounds can betransformed into the compounds of Formula I, II, III, V, VI, and VIIwherein T is —(CR^(a) ₂)_(n)CH(NR^(b)R^(c))— according to knownprocedures (Tetrahedron Lett. 37:407 (1996)).

For compounds of Formula I, II, III, V, VI, and VII wherein T is—(CO)(CR^(a) ₂)_(m)—, the phosphonate group can be introduced by anumber of known methods such as reacting a substituted benzoyl chloridewith diethylphosphonoacetic acid (Synthetic Commu. 30:609 (2000)) or aphosphonate copper reagent (Tetrahedron Lett. 31:1833 (1990)).Alternatively, coupling of triethyl phosphonate with a silyl enol ether(Synthetic Commu. 24:629 (1994)) or a α-bromobenzophenone (PhosphorusSulfur 90:47 (1994)) can also introduce the phosphonate group.

For compounds of Formula I, II, III, V, VI, and VII wherein T is—C(O)NH(CR^(b) ₂)(CR^(a) ₂)_(p)—, the phosphonate group can beintroduced by coupling reaction of a substituted benzoic acid and anaminophosphonate according to the standard amide bond formation methods(Tetrahedron Lett. 31:7119 (1990); Tetrahedron Lett. 30:6917 (1989); J.Org. Chem. 58:618 (1993)).

For compounds of Formula I, II, III, V, VI, and VII wherein T is—(CR^(a) ₂)C(O)(CR^(a) ₂)_(n)— or (CR^(a) ₂)_(n)C(O)(CR^(a) ₂), thephosphonate group can be introduced by reacting a benzyl bromide with afunctionalized phosphonate (Tetrahedron Lett. 30:4787 (1989)).Alternatively, a coupling reaction of a substituted phenylacetate andmethylphosphonate also yields the desired product (J. Am. Chem. Soc.121:1990 (1999)).

Construction of The Diaryl Ring

Compounds of Formula I, II, III, IIV, V, and VII wherein G is —O— can beprepared according to known methods. As described in Scheme 2, 2a isreacted with 2b at room temperature in the presence of Cu powder and asuitable base such as TEA, diisopropylamine or pyridine to provide thecoupling product 4 (J. Med. Chem. 38:695 (1995)). Deprotection of themethoxy group with suitable reagents such as boron tribromide, borontrichloride or boron trifluoride in CH₂Cl₂ gives the intermediate 5.Introduction of the phosphonate group followed by deprotection of thephosphonate ester as described in Scheme I leads to the desiredphosphonic acid 6. Those skilled in the art can use other known methodssuch as coupling of an arylboronic acid and a phenol in the presence ofCu(OAc)₂ (Tetrahedron Lett. 39:2937 (1998)), nucleophilic substitutionof a fluorobenzene (Synthesis-Stuttgart 1:63 (1991)) or iodobenzene (J.Am. Chem. Soc. 119:10539 (1997)) with a phenol and coupling of abromobenzene with a phenol in the presence of Pd₂(dba)₃ (TetrahedronLett. 38:8005 (1997)) to form the diaryl ether system.

For compounds of Formula I, II, III, IV, V, and VII wherein G is —CH₂—,the installation of the diaryl ring can be accomplished by a number ofknown methods. For example, as described in Scheme 3, benzyl alcohol 7is formed by treatment of 3a with n-BuLi at −78° C. in THF followed byreacting with 3b (Bioorg. Med. Chem. Lett. 10:2607 (2000)).Hydrogenolysis with Pd—C or dehydroxylation of benzyl alcohol 7 by NaBH₄(Synthetic Commu. 17:1001 (1987)) and (1-Bu)₃Al (Synthesis 736 (1987))followed by removal of the protecting group gives the diarylintermediate 8. Phosphonic acid 9 is formed from 8 according to the sameprocedures as described in Scheme 1. Alternatively, coupling of benzylbromide with an aryl Grignard reagent (Tetrahedron Lett. 22:2715(1981)), an arylboronic acid (Tetrahedron, Lett. 40:7599 (1999)) or azinc reagent (Chem. Lett. 11:1241 (1999)) and reduction of a diarylketone (J. Org. Chem. 51:3038 (1986)) are all widely used methods forthe construction of the diaryl ring.

For compounds of Formula I, II, III, IV, V, and VII wherein G is —S—,—S(═O)— or —S(═O₂)—, the formation of the diaryl ring can be achievedaccording to known methods. As illustrated in Scheme 4, 3a can bereacted with 4a in the presence of a catalyst such as Pd₂(dba)₃ or CuBrto provide the diaryl sulfide 10 (Tetrahedron 57:3069 (2001);Tetrahedron Lett. 41:1283 (2000)). Phosphonic acid 12 is formed from 10after removal of the protecting groups followed by the same proceduresas described in Scheme 1. The diaryl sulfide 10 can also be converted tothe sulfoxide 13 according to known methods (Synthetic Commu. 16:1207(1986); J. Org. Chem. 62:4253 (1997); Tetrahedron Lett. 31:4533 (1990)),which leads to the phosphonic acid 15 following the same procedures asdescribed in Scheme 1. Also, the biaryl sulfide 10 can be converted tothe sulfone (Tetrahedron Lett. 32:7353 (1991); J. Prakt. Chem. 160(1942)) which leads to the phosphonic acid (G is —S(═O₂)—) following thesame procedures as described above. In addition, nucleophilicsubstitution of chlorobenzene and bromobenzene with a thiol is also anefficient way to install the diaryl sulfide ring (J. Med. Chem. 31:254(1988); J. Org. Chem. 63:6338 (1998)).

For compounds of Formula I, II, III, IV, V, and VII wherein G is —NH— or—N(C₁-C₄ alkyl)-, the diarylamine backbone can be formed by a number ofkinown methods. Among those conditions, one widely used by those skilledin the art is the coupling reaction of an aniline with an aryl bromide(J. Org. Chem. 64:5575 (1999); J. Org. Chem. 62:6066 (1997); TetrahedronLett. 37:6993 (1996); Org. Lett. 1:2057 (1999)) or an aryl tosylate (J.Org. Chem. 62:1268 (1997)) in the presence of a catalyst such as PdCl₂or Pd₂(dba)₃. As illustrated in Scheme 5, the diarylamine intermediate16 can be prepared by coupling of bromide 3a and aniline 5a in thepresence of Pd₂(dba)₃. After removal of the protecting group, thediarylamine 17 is converted to the phosphonic acid 18 following the sameprocedures as described in Scheme 1. Alternatively, coupling of ananiline and aryl halide using other catalysts such as copper-bronze(Org. Synth. 2:446 (1943); J. Org. Chem. 20 (1955)) and Cu(OAc)₂ (J.Med. Chem. 1986, 4:470 (1986); Synthetic Commu. 26:3877 (1996)) toconstruct the diarylamine backbone is also a feasible approach.

For compounds of Formula I, II, III, IV, V, and VII wherein G is —CHF—or —CF₂—, the diaryl backbone can be established from the benzyl alcohol7. Accordingly, as described in Scheme 6, benzyl alcohol 7 can beconverted to the benzyl fluoride 19 by reacting with DAST in CH₂Cl₂according to known procedures (J. Chem. Soc., Chem. Commu. 11:511(1981); Tetrahedron Lett. 36:6271 (1995); Tetrahedron 14:2875 (1988)).Also, the benzyl alcohol 7 can be easily oxidized to the benzophenone 22according to known methods such as MnO₂ oxidation, PCC oxidation, Swemoxidation and Dess-Martin oxidation, which is subsequently converted tothe benzyl difluoride 23 by treatment with DAST (J. Fluorine 61:117(1993)) or other known reagents (J. Org. Chemn. 51:3508 (1986);Tetrahedron 55:1881 (1999)). After removal of the protecting groups, thebenzyl fluoride 20 and difluoride are converted to the desiredphosphonic acids following the same procedures as described in Scheme 1.

Compounds of Formula I, II, III, IV, V, and VII wherein G is —CH(OH)— or—C(O)— can be prepared from the intermediates 7 and 22. Removal of theprotecting groups of 7 and 22 followed by introduction of the phosphateand deprotection as described in Scheme I provides the desiredphosphonic acids of Formula I.

Synthesis of compounds of Formula IV

The synthesis of compounds of Formula IV where A is —NH— and B is —H— or—C-alkyl- can be accomplished from the corresponding amino diarylprecursor I using the well-known, to those skilled in the art, Fisherindole synthesis (Scheme 6a) (Phosphorus and Sulfur 37:41-63 (1988)).Alternatively, the aryl-indole scaffold is constructed using theprocedures previously described and the phosphonic acid moiety isintroduced by making the anion next to the nitrogen of the indolederivative, protected at the nitrogen, with a base such as BuLi andquenching the anion with diethyl chlorophosphate. Further protectinggroup and functional group manipulations of intermediates 2 providecompounds of Formula IV.

Compounds of Formula IV where A is —O— and B is —CH— are synthesizedfrom the corresponding diaryl phenol precursor 3 and ring cyclizationwith the dimethylacetal of bromoacetaldehyde to give benzofuran 4(Scheme 6b) (J. Chem. Soc., Perkin Trans. 1, 4:729 (1984)). Thephosphonic acid moiety can then be introduced by making the anion nextto the oxygen of the benzo[t]ran with a base such as BuLi and quenchingthe anion with diethyl chlorophosphate to provide phosphonate 5. Furtherprotecting group and functional group manipulations of intermediate 5provides compounds of Formula II.

Compounds of Formula IV where A is —NH—, —O— or —S— and B is —N— can bemade from condensation of the corresponding diaryl precursor 6 with anorthoformate such as triethyl orthoformate in presence of acid to giveheterocycle 7 (Org. Prep. Proced. 1st., 22(5):613-618 (1990)). Thephosphonic acid moiety can then be introduced by making the anion at the2-position of the heterocycle 7 with a base such as BuLi and quenchingthe anion with diethyl chlorophosphate to give phosphonate 8. Furtherprotecting group and functional group manipulations of intermediates 8provide compounds of Formula II.

Synthesis of Compounds of Formula V

The general synthesis of compounds of Formula V wherein G is —O—, —S— or—NH— utilizes the displacement of an appropriately substituted phenol,thiophenol or aniline 1 with a pentasubstituted pyridine such as3,5-dichloro-2,4,6-trifluoro-pyridine 2 to provide intermediate 3(Scheme 6d) (Org. Prep. Proced. Int. 32(5):502-504 (2000)). Subsequentdisplacement of the 2-fluoro and 6-fluoro substituents on the pyridinering with nucleophiles 4 and HR7 sequentially provide intermediates 5and 6. Examples of suitable nucleophiles, include but are not limitedto, diethyl hydroxymethyl-phosphonate and diethylaminomethyl-phosphonate. Example of reactants HR7, include but are notlimited to, alkylthiol, sodium alkoxide, alkylamine or benzylamine.Compounds of Formula V where 0 is —S(═O)— and —S(═O)₂— can be derivedfrom intermediates 5 and 6 when G is —S— via oxidation with an oxidizingagent such as mCPBA. Further protecting group and functional groupmanipulations of intermediates 5 and 6 will provide compounds of FormulaV.

Compounds of Formula V wherein G is —CH₂— or —C(O)— are synthesizedaccording to scheme 6e. Condensation of benzyl cyanide 7 withpentasubstituted pyridine 2 provide intermediate 8. Displacement of2-fluoro with reagent 4 gives intermediate 9. Oxidation of benzylcyanide 9 provides keto derivative 10 which after deprotection andfunctional group manipulation gives a compound of Formula V.Alternatively, reductive deoxygenation of keto intermediate followed bydeprotection and functional group manipulation gives a compound ofFormula V.

Synthesis of Compounds of Formula VI

Biaryl compounds of formula VI can be synthesized by coupling a boronicacid, or its pinacol ester, of a properly derivatized naphtyl moietywith a properly substituted aryl iodide, bromide or triflate usingconditions commonly employed for a Suzuki reaction (Hoye et al., J. Org.Chem. 61:7940 (1996); Hoye et al, Tetrahedron Lett. 3:3097 (1996); Antonet al., Chem. Ber. 125:2325 (1992); Anton et al., Chem. Ber. 126:517(1993); Shich et al., J. Org. Chem. 57:379 (1992); Nakano et al.,Synthesis 12:1425 (1997); Kumar, J. Org. Chem. 62:8535 (1997); Blettneret al., J. Org. Chlem. 64:3885 (1999).

Synthesis of Phosphonic Acid Monoesters

Compound of the invention where the acidic group is a phosphonic acidmonoester may be prepared ftom the diester intermediate, used for thesynthesis of phosphonic acid thyromimetic, by monosaponification.Monohydrolysis of one of the ester groups on the phosphonate may beaccomplished by treatment of phosphonate diesters with aqueous alkalinesolution such as NaOH, KOH or LiOH at rt or while heating. Sodium azidecan also be used in DMF (Bioorg. Med. Chem. Lett. 14(13),3559-62 (2004))to accomplished the monosaponification. Alternatively, organic basessuch as morpholine or N-methyl-piperazine can be used to hydrolyze oneof the phosphonate ester groups (Synth. Comm. 34(2):331-344 (2004)).

Synthesis of Phosphinic Acids

The introduction of a phosphinic acid group can generally beaccomplished according to known methods. An efficient way to synthesizephosphinic acid is to convert a phosphonate diester to its correspondingmonochloridate-monoester using one of many chlorinating agents such asPCl₅ (Can. J. Chem. 76(3):313-18 (1998)), oxalyl chloride (TetrahedronLett. 44(12):1445-48 (2003)), thionyl chloride (J. Med. Chem.45(4):919-29 (2002)) or phosgene (Recl. Trav. Chim. Pays-Bas 78:59-61(1959)) and to introduce the carbon-based substituent on the phosphorusatom via a Grignard reagent (J. Chem. Soc. Perkin Trans. 1 17:2179-86(1996)), a lithium anion (J. Med. Chem. 33(11):2952-56 (1990)) or anenolate (Bioorg Med. Chem. 5(7):1327-38 (1997)) to produce the desiredphosphinate ester. The phosphinic acid is then generated bysaponification with aqueous NaOH, KOH or LiOH or using one of the manymethods known to deprotect phosphonic acids such as TMSBr or TMSC1/KI.Alternatively, phosphinic acids can be generated from phosphonic acidmonoesters by making the monochloridate-monoester with chlorinatingreagents such as thionyl chloride or oxalyl chloride, and introducingthe substituent on the phosphorus as above.

Compounds of Formula I wherein T is —O(CR^(b) ₂)(CR^(a) ₂)_(n)—,—S(CR^(b) ₂)(CR^(a) ₂)_(n)— or —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)— may beprepared by coupling a phenol, thiophenol, or aniline with a phosphinateester component such as I(CR^(b) ₂)(CR^(a) ₂)_(n)P(O)(OEt)(lower alkyl),TsO(CR^(b) ₂)(CR^(a) ₂)_(n)P(O)(OEt)(lower alkyl), or TfO(CR^(b)₂)(CR^(a) ₂)_(n)P(O)(OEt)(lower alkyl) in the presence of a base such asNaH, K₂CO₃, Cs₂CO₃, KO-t-Bu or TEA (J. Am. Chem. Soc. 114(19):7604-06(1992)). These phosphinate ester components can be synthesized bycondensation of a mono phosphinate, such as ethyl methylphosphinate,with formaldehyde in presence of a base such Et₃N (Tetrahedron Asymetry13(7):735-38 (2002)).

Compounds of Formula I wherein T is —N(R^(b))C(O)(CR^(a) ₂)_(n)— can beprepared by coupling an aniline with a carboxylic acid containing aphosphinate moiety (lower alkyl)(EtO)P(O)(CR^(a) ₂)₁₋₂CO₂H in thepresence of DCC or EDC according to the known methods (Syn. Lett.9:1471-74 (2002)) or converting an aniline to a phenyl isocyanate withdiphosgene followed by reacting with a mono-substituted phosphinate (Zh.Obshch. Khim. 26:3110-11 (1956)). Alternatively, condensation of thecarbon anion of a phosphinate provides the β-amido-phosphinate (J. Org.Chem. 45(12):2519-22 (1980)).

For compounds of Formula I wherein T is —(CR^(a) ₂)_(k)—, thephosphonate group can be introduced by a number of known methods. Forexample, the coupling reaction of a phenyl halide (Synthesis, 14:2216-20(2003)) with mono-substituted phosphinate in the presence of a Pdcatalyst is widely used within the art (when k is 0). Other methods suchas Michaelis-Arbuzov can also be an efficient way to introduce thephosphinate group by coupling a benzyl or arylalkyl halide with aphosphonite diester (when m is 1-3) (Org. Lett. 5(17):3053-56 (2003)).Alternatively, phosphinates can be synthesized by coupling ofmono-substituted phosphinate esters with olefins, such as styrenes, inthe presence of t-Bu₂O₂ (Justus Liebig Ann. Chem. 741-50 (1974)) or(PhCO)₂O₂ (J. Gen. Chem. USSR 30:2328-32 (1960)).

For compounds of Formula I wherein T is —(CR^(a) ₂)_(n)—CR^(b)—CR^(b)—,the phosphonate group can be introduced by coupling an acetylene and amonosubstituted phosphinate in the presence of a catalyst such asNi(PPh₂Me), Ni(cod)₂ (J. Am. Chem. Soc. 126(16):5080-81 (2004)) orMe₂Pd(PPh₂)₂ (J. Am. Chem. Soc. 124(15):3842-43 (2002)). For compoundsof Formula I wherein T is —CR^(b)═CR^(b)—(CR^(a) ₂)_(n)— or —(CR^(a)₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, the phosphinate group can be introduced byMichaelis-Arbuzov reaction of the corresponding olefinic halide with aphosphonite diester.

For compounds of Formula I wherein T is —(CR^(a) ₂)_(m)(CO)—, thephosphinate group can be introduced by reacting a phosphonite diesterwith an acyl chloride in the presence of sodium (J. Gen. Chem. USSR34:4007-9 (1964)) or an aldehyde in the presence of lithium phenoxidefollowed by an oxidation (Tetrahedron Lett. 45(36:6713-16 (2004)).Alternatively, treatment of an acyl chloride with a phosphonate diesterprovides access to α-keto-phosphinate (J. Chem. Soc. Perkin Trans. 1,659-66 (1990)).

For compounds of Formula I wherein T is —(CO)(CR^(a) ₂)_(m)—, thephosphinate group can be introduced by a number of known methods such asreacting a substituted benzoate ester with the anion of a phosphinatemade with a base such as BuLi or LDA (Bull. Soc. Chim. Fr. 3494-3502(1972)). Alternatively, coupling the anion of a phosphinate with asubstituted benzaldehyde followed by an oxidation provides access to theβ-keto-phosphinate (J. Med. Chem. 38(17):3297-3312 (1995)).

For compounds of Formula I wherein T is —C(O)NH(CR^(b) ₂)(CR^(a)₂)_(p)—, the phosphonate group can be introduced by a coupling reactionof an aminophosphinate (Synthesis 1074-76 (1995)) with substitutedbenzoyl chloride (J. Organomet. Chem. 178:157-69 (1979)) or asubstituted benzoic acid according to the standard amide bond formationmethods (Bioorg. Med. Chem. Lett. 6(14):1629-34 (1996)).

For compounds of Formula I wherein T is —(CR^(a) ₂)C(O)(CR^(a) ₂)_(n)—,the phosphinate group can be introduced by reacting a substitutedphenylacetate with a functionalized anion of a phosphinate made with abase such as BuLi or LDA (Bull. Soc. Chim. Fr. 3494-3502 (1972)).

Synthesis of Cyclic Phosphinic Acids and Cyclic Phosphonic Acids

Cyclic phosphinic acids can be synthesized starting from a1,2-dicarboxylate-benzene precursor (J. Am. Chem. Soc. 101:7001-08(1979)) which is reduced to the di-benzylic alcohol and brominated withPBr₃ to give the di-benzylic bromide precursor (Synth. Commun.14(6):507-514 (1984)). Double Arbuzov condensation of the di-benzylicbromide with bis(trimethylsilyloxy)phosphine, made from the reaction ofammonium hypophosphite and hexamethyldisilazane, provides the cyclicphosphinate ester (J. Org. Chem. 60:6076-81 (1995)) which can beconverted to the phosphinic acid by saponification with NaOH or TMSBr.Alternatively, the di-benzyl bromide precursor can be obtained bybromination of a substituted 1,2-dimethyl benzene with bromine orN-bromosuccinimide (J. Chem. Soc. 3358-61 (1959)) or directbromomethylation by reacting formaldehyde and HBr in presence of aceticacid (J. Phys. Chem. 108(4):5145-55 (2004)).

Cyclic phosphonates can be synthesized by condensing a di-benzylicalcohol with trimethylphosphite (Bull. Acad. Sci. USSR Div. Chem. Sci.37:1810-14 (1988)) to get the cyclic phosphite which is then convertedto the cyclic phosphonate by a photo-Arbuzov rearrangement (J.Organomet. Chem. 646:239-46 (2002)). Alternatively, the cyclic phosphitecan be obtained by condensing a di-benzylic alcohol with HMPT (J. Org.Chem. 57(10):2812-18 (1992)) or diethylphosphoramidous dichloride to geta cyclic phosphoramidous diester which is then converted to the cyclicphosphite by reaction with an alcohol, such as methanol or phenol, inthe presence of an activating agent such as tetrazole ormethylthio-tetrazole (J. Org. Chem. 61:7996-97 (1996)). The phosphonicacid is then obtained by selective monosaponification.

Synthesis of Prodrugs of Phosphinic Acids and Phosphonate Monoesters

Prodrugs can be introduced at different stages of the synthesis. Mostoften these prodrugs are made from the phosphonic acid monoesters andphosphinic acids because of their lability.

Phosphinic acids and phosphonic acid monoesters can be alkylated withelectrophiles such as alkyl halides and alkyl sulfonates undernucleophilic substitution conditions to give phosphonate esters. Forexample, compounds of Formula I wherein YR¹¹ is an acyloxyalkyl groupcan be prepared by direct alkylation of compounds of Formula I with anappropriate acyloxyalkyl halide (e.g., Cl, Br, I; Phosphorus Sulfur54:143 (1990); Synthesis 62 (1988)) in the presence of a suitable base(e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents suchas DMF (J. Med. Chem. 37:1875 (1994)). The carboxylate component ofthese acyloxyalkyl halides includes but is not limited to acetate,propionate, isobutyrate, pivalate, benzoate, carbonate and othercarboxylates.

Dimethylformamide dialkyl acetals can also be used for the alkylation ofphosphinic acids and phosphonic acid monoesters (Collect. Czech Chem.Commu. 59:1853 (1994)). Compounds of Formula I wherein YR¹¹ is a cycliccarbonate, a lactone or a phthalidyl group can also be synthesized bydirect alkylation of the free phosphonic acids with appropriate halidesin the presence of a suitable base such as NaH or diisopropylethylamine(J. Med. Chem. 38:1372 (1995); J. Med. Chem. 37:1857 (1994); J. Pharm.Sci. 76:180 (1987)).

Alternatively, these phosphinate and monoester phosphonate prodrugs canbe synthesized by the reactions of the correspondingchlorophospho(i)nate and an alcohol (Collect Czech Chem. Cominun.59:1853 (1994)). For example, a chlorophospho(i)nate is reacted withsubstituted phenols and arylalkyl alcohols in the presence of a basesuch as pyridine or TEA to give the compounds of Formula I wherein YR¹¹is an aryl group (J. Med. Chem. 39:4109 (1996); J. Med. Chem. 38:1372(1995); J. Med. Chem. 37:498 (1994)) or an arylalkyl group (J. Chem.Soc. Perkin Trans. 1 38:2345 (1992)). The disulfide-containing prodrugs(Antiviral Res. 22:155 (1993)) can be prepared from achlorophospho(i)nate and 2-hydroxyethyldisulfide under standardconditions. Chlorophospho(i)nates are also useful for the preparation ofvarious phospho(i)namides as prodrugs. For example, treatment of achlorophospho(i)nate with ammonia gives the phospho(i)namide.

Such reactive dichlorophosphonates can be generated from thecorresponding phosphinic acids and phosphonic acid monoesters with achlorinating agent (e.g., thionyl chloride, J. Med. Chem. 1857 (1994);oxalyl chloride, Tetrahedron Lett. 31:3261 (1990); phosphorouspentachloride, Synthesis 490 (1974)). Alternatively, adichlorophosphonate can be generated from its corresponding silylphosphinate ester or phosphonic acid monester (Synth. Commu. 17:1071(1987)) or alkyl phosphinate esters (Tetrahedron Lett. 24:4405 (1983);Bull. Soc. Chim. 130:485 (1993)).

Chlorophospho(i)nates are also useful for the preparation of variousphosphonamides as prodrugs. For example, treatment of achlorophospho(i)nate with an amine (e.g. an amino acid alkyl ester suchas L-alanine ethyl ester) in the presence of a suitable base (e.g.triethylamine, pyridine, etc.) gives the correspondingphosphor(i)namide. Direct couplings of phosphinic acids or phosphonicacid monoesters with an amine (e.g. an amino acid alkyl ester such asL-alanine ethyl ester) are also reported to give the correspondingamidate under Mukaiyama conditions (J. Am. Chem. Soc. 94:8528 (1972)).

The SATE (S-acetyl thioethyl) prodrugs can be synthesized by thecoupling reaction of the phosphinic acids or phosphonic acid monoestersof Formula I and S-acyl-2-thioethanol in the presence of DCC, EDCI orPyBOP (J. Med. Chem. 39:1981 (1996)).

Preparation of Key Precursors

A. Preparation of Compounds with Substituents on the Ring

Starting material and key intermediates required for the synthesis ofthe compounds in this invention are either commercially available orprepared using an existing method in the literature or a modification ofa known method. Syntheses of some of those compounds are describedherein.

Precursor 2a is prepared by reacting an anisole with iodinetrifluoroacetate according to the reference procedures (J. Med. Chem.38:695 (1995)). Anisoles with different R³ and R⁴ groups are eithercommercially available or can be prepared according to the literatureprocedures (e.g., J. Med. Chem. 32:320 (1989)).

Starting material 2b is either commercially available or preparedaccording to known procedures. For example, compounds of 2b wherein FGis NH₂-derived group can be prepared by reacting 3a with benzophenoneimine in the presence of a Pd catalyst such as Pd₂(dba)₃ or Pd(OAc)₂(Tetrahedron Lett. 38:6367 (1997); J. Am. Chem. Soc. 120:827 (1998)).Compounds of 2b wherein FG is S-derived group can be prepared byreacting a feasible 4-aminoanisole with NaNO₂ and potassium ethylxanthate (J. Am. Chem. Soc. 68 (1946); Heterocycles 26:973 (1987)).

The useful precursor 3a can either be commercially available reagents orprepared according to the existing methods. As described in Scheme 7, asimple protection of commercially available 4-bromophenol 7b withdifferent R³ and R⁴ groups according to the procedures known in the artleads to 3a. Compound 3a can also be prepared by bromination ofprotected phenol 7d (J. Org. Chem. 53:5545 (1988); J. Org. Chem. 59:4473(1994); Synthesis-Stuttgart 10:868 (1986)). Introduction of various R³and R⁴ groups to 4-bromophenol 7a can be carried out to give 7b whichleads to 7a after protection (Tetrahedron Lett. 36:8453 (1995); J.Heterocyclic Chem. 28:1395 (1991); J. Fluorine Chem. 40:23 (1988);Synthesis-Stuttgart 11:1878 (1999); Synthetic Commu. 16:681 (1986)). 7bcan also be prepared by the bromination of phenol 7c (J. Comb. Chem.2:434 (2000); Chem. Soc. Jpn. 61:2681 (1988); Synthesis-Stuttgart 5:467(1992); Org. Synth. 72:95 (1993)).

A number of methods are available for the preparation of thebenzaldehyde 3b. As illustrated in Scheme 8, bromobenzene 8a can beconverted to benzaldehyde 3b by reacting with DMF (Aust. J. Chem. 51:177(1998); Bioorg. Med. Chem. Lett. 10:2607 (2000)) or carbon monoxide inthe presence of a palladium catalyst (Bull. Chem. Soc. Jpn 67:2329(1994)). 3b may be formed by oxidation of benzyl alcohol 8c using commonmethods such as MnO₂ oxidation, PCC oxidation, Swern oxidation andDess-Martin oxidation. Reduction of benzonitrile 8b and benzoyl chloride8d also produces benzaldehyde 3b (Org. Synth. 3:551 (1995); J. Org.Chem. 46:602 (1981)).

For some of the compounds of Formula II-V, the R³ and R⁴ groups can beintroduced after the biaryl ring backbone is installed. As illustratedin Scheme 9, the intermediate 4 (R³, R⁴═H) is converted to thebenzylaldehyde 26 upon treatment with SnCl₄ and methoxymethyldichloride. Various alkyl groups (C₁-C₁₂) are introduced by reacting thebenzylaldehyde 26 with a Wittig reagent followed by the reduction of theresulting alkene with Et₃SiH to afford the intermediate 27 (J. Med.Chem. 31:37 (1988)). Also, benzylaldehyde 31 can be oxidized by NaOCl₂to give the benzoic acid 29 (Bioorg. Med. Chem. Lett. 13:379 (2003))which can be reacted with an alcohol or amine under standard conditionsto give the ester or amide 30. Intermediates 27 and 30 can be convertedto the corresponding phosphonic acids 28 and 33 following the sameprocedures as described in Scheme 2. In addition, deprotection ofintermediate 4 provides the phenol 32 which can be converted to avariety of sulfonamides 33 upon treatment with ClSO3H and an amine.Phosphonic acids (R³═S(═O)₂NR^(f)R^(g)) can be formed following the sameprocedures as described in Scheme 1.

B. Preparation of 1,3-Diols

Various methods can be used to prepare 1,3-propanediols such asI-substituted, 2-substituted, 1,2- or 1,3-annulated 1,3-propanediols.

1. 1-Substituted 1,3-propanediols

1,3-Propanediols useful in the synthesis of compounds in the presentinvention can be prepared using various synthetic methods. As describedin Scheme 10, additions of an aryl Grignard to a 1-hydroxy-propan-3-algive 1-aryl-substituted 1,3-propanediols (path a). This method issuitable for the conversion of various aryl halides to1-arylsubstituted-1,3-propanediols (J. Org. Chem. 53:911 (1988)).Conversions of aryl halides to 1-substituted 1,3-propanediols can alsobe achieved using Heck reactions (e.g., couplings with a 1,3-diox-4-ene)followed by reductions and subsequent hydrolysis reactions (TetrahedronLett. 33:6845 (1992)). Various aromatic aldehydes can also be convertedto 1-substituted-1,3-propanediols using alkenyl Grignard additionreactions followed by hydroboration-oxidation reactions (path b).

Aldol reactions between an enolate (eg., lithium, boron, tin enolates)of a carboxylic acid derivative (e.g., tert-butyl acetate) and analdehyde (e.g., the Evans's aldot reactions) are especially useful forthe asymmetric synthesis of enantioenriched 1,3-propanediols. Forexample, reaction of a metal enolate of t-butyl acetate with an aromaticaldehyde followed by reduction of the ester (path e) gives a1,3-propanediol (J. Org. Chem. 55:4744 (1990)). Alternatively,epoxidation of cinnamyl alcohols using known methods (e.g., Sharplessepoxidations and other asymmetric epoxidation reactions) followed byreduction reactions (e.g., using Red-A1) give various 1,3-propanediols(path c). Enantioenriched 1,3-propanediols can be obtained viaasymmetric reduction reactions (e.g., enantioselective boranereductions) of 3-hydroxy-ketones (Tetrahedron Lett. 38:761 (1997)).Alternatively, resolution of racemic 1,3-propanediols using variousmethods (e.g., enzymatic or chemical methods) can also giveenantioenriched 1,3-propanediol. Propan-3-ols with a 1-heteroarylsubstituent (e.g., a pyridyl, a quinolinyl or an isoquinolinyl) can beoxygenated to give 1-substituted 1,3-propanediols using N-oxideformation reactions followed by a rearrangement reaction in aceticanhydride conditions (path d) (Tetrahedron 37:1871 (1981)).

2. 2-Substituted 1,3-propanediols

A variety of 2-substituted 1,3-propanediols useful for the synthesis ofcompounds of Formula I-VII can be prepared from various other1,3-propanediols (e.g., 2-(hydroxymethyl)-1,3-propanediols) usingconventional chemistry (Comprehensive Organic Transformations, VCH, NewYork, 1989). For example, as described in Scheme 11, reductions of atrialkoxycarbonylmethane under known conditions give a triol viacomplete reduction (path a) or a bis(hydroxymethyl)acetic acid viaselective hydrolysis of one of the ester groups followed by reduction ofthe remaining two other ester groups. Nitrotriols are also known to givetriols via reductive elimination (path b) (Synthesis 8:742 (1987)).Furthermore, a 2-(hydroxymethyl)-1,3-propanediol can be converted to amono acylated derivative (e.g., acetyl, methoxycarbonyl) using an acylchloride or an alkyl chloroformate (e.g., acetyl chloride or methylchloroformate) (path d) using known chemistry (Protective Groups InOrganic Synthesis; Wiley, New York, 1990). Other functional groupmanipulations can also be used to prepare 1,3-propanediols such asoxidation of one the hydroxymethyl groups in a2-(hydroxymethyl)-1,3-propanediol to an aldehyde followed by additionreactions with an aryl Grignard (path c). Aldehydes can also beconverted to alkyl amines via reductive amination reactions (path e).

3. Annulated 1,3-propane diols

Compounds of Formula I-VII wherein V and Z or V and W are connected byfour carbons to form a ring can be prepared from a 1,3-cyclohexanediol.For example, cis, cis-1,3,5-cyclohexanetriol can be modified to givevarious other 1,3,5-cyclohexanetriols which are useful for thepreparations of compounds of Formula I wherein R¹¹ and R¹¹ together are

wherein together V and W are connected via 3 atoms to form a cyclicgroup containing 6 carbon atoms substituted with a hydroxy group. It isenvisioned that these modifications can be performed either before orafter formation of a cyclic phosphonate 1,3-propanediol ester. Various1,3-cyclohexanediols can also be prepared using Diels-Alder reactions(e.g., using a pyrone as the diene: Tetrahedron Lett. 32:5295 (1991)).2-Hydroxymethylcyclohexanols and 2-hydroxymethylcyclopentanols areuseful for the preparations of compounds of Formula I wherein R¹¹ andR¹¹ together are

wherein together V and Z are connected via 2 or 3 atoms to form a cyclicgroup containing 5 or 6 carbon atoms. 1,3-Cyclohexanediol derivativesare also prepared via other cycloaddition reaction methodologies. Forexample, cycloadducts from the cycloaddition reactions of a nitrileoxide and an olefin can be converted to a 2-ketoethanol derivative whichcan be further converted to a 1,3-propanediol (including1,3-cyclohexanediol, 2-hydroxymethylcyclohexanol and2-hydroxymethylcyclopentanol) using known chemistry (J. Am. Chem. Soc.107:6023 (1985)). Alternatively, precursors to 1,3-cyclohexanediol canbe made from quinic acid (Tetrahedron Lett. 32:547 (1991)).

EXPERIMENTAL Example 1

Examples of the method of the invention includes the following. It willbe understood that these examples are exemplary and that the method ofthe invention is not limited solely to these examples.

For the purposes of clarity and brevity compounds are referred to bycompound numbers (from the Table below) in the biological examplesbelow.

Compound Structure Number

17

 7

 6

cis-13-1

TRIAC

18

Example A Chronic Exposure to Thyroid Receptor Agonists in Normal Rats

The purpose of these studies was to compare the difference in efficacyto clear liver triglyceride content between T3 and various T3 mimeticsthat are carboxylic acids and T3 mimetics that are phosphonic acids. Inone example, T3 and Compounds 7 and 17, which differ only in that forCompound 7, the X moiety of Formula II is —P(O)OH₂ and for Compound 17,X is —C(O)OH, were compared. In the same example TRIAC and Compound 6,which differ only in that for Compound 6, X is —P(O)OH₂ and for TRIAC, Xis —C(O)OH, were compared. Efficacy was measured by analyzing totalliver triglycerides.

Methods: Normal rats (Sprague-Dawley) were maintained on a standarddiet. Compounds 7, 17, 6, TRIAC or T3 were administered by continuousinfusion using an osmotic pump (Alzet; subcutaneous implant) at a doseof 1 mg/kg/day. The compounds were dissolved in 0.1N NaOH solution andthe pH adjusted to 7.4-8.0. The compounds were brought up to anappropriate volume using PBS and BSA to maintain solubility within thepump. The compounds were chemically stable in the excipient at 37° C.for 7 days. Body weights were measured and the change from the startingbody weight was calculated. The 4.5% reported for the vehicle animalsrepresent a 4.5% increase in body weight over the course of theexperiment.

Sections of liver were removed and frozen. Liver triglycerides wereanalyzed following lipid extraction by the Bligh Dyer method (Bligh andDyer, Can. J. Med. Sci. 37(8):911-7 (1959), incorporated herein byreference). Total triglycerides were analyzed in the liver extracts byan enzymatic assay (Thermo Electron Corporation). Total lipid wasnormalized to initial liver weight and triglyceride content wasnormalized to liver weight. mGPDH activity was analyzed in isolatedmitochondria using 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride as the terminal electron acceptor (Gardner R^(S),Analytical Biochemistry 59:272 (1974)). Commercially available GPDH wasused in each assay as a standard (Sigma, St. Louis, Mo.).

Results: T3 did not significantly decrease liver triglyceride content.However, all synthetic thyroid receptor ligands tested unexpectedly andsignificantly decrease hepatic triglyceride content. T3, compound 17 andTRIAC all produced a loss of body weight over the course of theexperiment, in agreement with previously reported results.

TABLE 2 Body Weight Liver mGPDH Triglycerides (% change activityCompound (mg/g liver) from start) (% vehicle) vehicle 5.3 ± 1.5  4.5 ±2.4 100 ± 4  T3 3.6 ± 0.6 −8.2 ± 1.5 406 ± 54 17  1.8 ± 0.3 −5.4 ± 1.0426 ± 45 7 1.3 ± 0.4  9.1 ± 1.5 399 ± 40 TRIAC 1.5 ± 0.4 −1.7 ± 0.6 384± 28 6 1.3 ± 0.2  8.7 ± 0.8 291 ± 37

Conclusion: synthetic thyroid receptor ligands, but not T3, decreasehepatic triglyceride content, while all thyroid receptor ligandsincrease mitochondrial activity.

Example B Chronic Exposure to Thyroid Receptor Agonists in ob/ob Mice

The purpose of these studies was to compare the difference in efficacyto clear liver triglyceride content between Compound cis-13-1 and T3 inob/ob mice.

Methods: ob/ob mice were maintained on a standard diet. Compoundcis-13-1 was administered at doses of 3, 10 and 30 mg/kg/d orally in aCMC suspension. T3, 100 nmole/kg/d, was administered as an aqueoussolution subcutaneously. Liver triglycerides were analyzed as describedin example A. Epididymal fat pads were removed and weighed. Clinicalchemistry analysis was performed by LabCorp (San Diego, Calif.).

Results: T3 did not significantly decrease liver triglyceride content(FIG. 1). However, Compound cis-13-1 decreased hepatic triglyceridecontent at 10 and 30 mg/kg/d (FIG. 1). Compound cis-13-1 did notdecrease epididymal fat pad (EFP) weight. T3 significantly decreased EFPweight, consistent with a well described effect of T3 on lipolysis.Treatment of ob/ob mice for 9 weeks with cis-13-1 caused a >50% decreasein ALT levels from 634 IU/L in the vehicle treated group, indicating animprovement in liver function.

TABLE 3 Treatment Liver Trigs (mg/g) EFP weight (g) Vehicle 109 ± 6  4.5± 0.2 T3 86 ± 5  2.0 ± 0.1* cis-13-1  3 87 ± 6 4.4 ± 0.1 10  66 ± 10*4.7 ± 0.1 30  59 ± 6* 4.4 ± 0.1

Conclusion: Synthetic thyroid receptor ligands, but not T3, decreasehepatic triglyceride content following long-term administration.

Example C Chronic Exposure to Thyroid Receptor Agonists in ZDF Rats

The purpose of these studies was to compare the difference in efficacyto clear liver steatosis between Compounds cis-13-1 and 18 in Zuckerdiabetic fatty (ZDF) rats.

Methods: ZDF rats were maintained on a standard diet (5008). Compoundscis-13-1 or 18 were administered orally at the indicated doses using aCMC suspension. Liver steatosis was analyzed visually following H&Estaining of paraffin embedded liver sections. TSH was measured using arodent specific kit (Amersham Biosciences). At the end of theexperiment, the left ventricle was cannulated with a high fidelitycatheter-tip transducer (Millar) via the right carotid artery. Leftventricle pressure, its first derivative (LV dP/dt), lead I ECG, andheart rate triggered off the ECG waveform, were recorded.

Results: Compounds cis-13-1 and 18 visually decreased hepatic steatosiscompared to control in ZDF rats (FIGS. 2A-2D). No significant decreasesin TSH were observed following 4 weeks of treatment with cis-13-1. Whenheart rates and other cardiovascular parameters were measured, therewere no significant changes from vehicle in any parameter in animalstreated with cis-13-1.

Conclusion: Synthetic thyroid receptor ligands decrease hepaticsteatosis following long-term administration in ZDF rats. Further, thedecrease in steatosis occurred with a suitable safety profile regardingTSH and cardiovascular changes.

Example D Chronic Exposure to Thyroid Receptor Agonists in DIO Mice

The purpose of these studies was to compare the ability of Compoundcis-13-1 to clear liver steatosis in diet induced obesity (DIO) mice.

Methods: C57B16 mice were maintained on a 60% Kcal from fat diet.Compound cis-13-1 was administered at doses of 30 mg/kg/d orally in aCMC suspension for 10 weeks. Liver steatosis was analyzed visuallyfollowing H&E staining of paraffin embedded liver sections. TSH wasmeasured using a rodent specific kit (Amersham Biosciences). Heart rateswere measured using a Lead I ECG with the heart rate calculated from theECG waveform.

Results: Compound cis-13-1 decreased hepatic steatosis in DIO micefollowing 10 weeks of treatment (FIGS. 3A and 3B). There were noabnormalities in the ultrastructure of mitochondria from DIO micetreated with cis-13-1. No significant decreases in TSH were observedfollowing 10 weeks of treatment with cis-13-1. When heart rates weremeasured, there was no significant change in heart rate with cis-13-1.

Conclusion: Compound cis-13-1 decreases hepatic steatosis followinglong-term administration. Further, the decrease in steatosis occurredwith a suitable safety profile regarding TSH and cardiovascular changes.

Example E Chronic Exposure to Thyroid Receptor Agonists in Normal Mice

The purpose of these studies was to compare the ability of Compoundcis-13-1 to change liver gene expression.

Methods: C57BI6 mice were maintained on a normal rodent diet. Compoundcis-13-1 was administered at doses of 30 mg/kg/d orally in a CMCsuspension for 1 week. Changes in levels of mRNA for liver and heartgenes are analyzed using reverse transcriptase followed by real-time PCRanalysis. The analysis is performed using an iCycler instrument (Biorad)and appropriate primers by means of standard methodology (e.g., Schwab DA et al. Life Sciences 66:1683-94 (2000)). The amounts of mRNA arenormalized to an internal control, typically, cyclophilin.

Results: Compound cis-13-1 increased CPT-1 expression 3.5-fold in normalmice, to a level similar to that observed with T3.

Conclusion: Compound cis-13-1 can increase mitochondrial liver geneexpression.

OVERALL CONCLUSIONS

Compounds cis-13-1,7,6, TRIAC, 17 and 18 decreased either hepatictriglyceride content or visually decreased hepatic steatosis in severalanimal models.

In either rats or mice treated with T3, no significant changes inhepatic triglyceride content were observed. In multiple models, T3produced the expected changes. In normal rats, T3 (a) decreased bodyweight; and (b) increased mGPDH activity. In ob/ob mice, epididymal fatpad weight was decreased, consistent with an increase in lipolysis.Therefore, in the experimental models, T3 retained expected physiologiceffects without producing a change in hepatic steatosis.

Synthetic thyroid hormone ligands, but not naturally occurringtriiodothyronine, can be useful for clearance of hepatic steatosis.

Having now fully described the invention, it will be understood by thoseof ordinary skill in the art that the same can be performed within awide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1. A method of decreasing fat content in the liver of an animal,comprising administering to said animal a therapeutically effectiveamount of a thyromimetic compound or a pharmaceutically acceptable saltthereof, wherein said compound binds to a thyroid receptor.
 2. A methodof preventing, treating, or ameliorating a fatty liver disease in ananimal, comprising administering to said animal a therapeuticallyeffective amount of a thyromimetic compound or a pharmaceuticallyacceptable salt thereof, wherein said compound binds to a thyroidreceptor.
 3. The method of claim 2 wherein said fatty liver disease isselected from the group consisting of steatosis, non-alcoholic fattyliver disease, and non-alcoholic steatohepatitis.
 4. The method of claim1 or 2 wherein said compound binds to a thyroid receptor with a Ki of ≦1μM.
 5. The method of claim 4 wherein said thyroid receptor is TRα1. 6.The method of claim 4 wherein said thyroid receptor is TRβ1.
 7. Themethod of claim 4 wherein said compound binds to a thyroid receptor witha Ki of ≦100 nM.
 8. The method of claim 7 wherein said thyroid receptoris TRα1.
 9. The method of claim 7 wherein said thyroid receptor is TRβ1.10. The method of claim 1 or 2, wherein said compound activates saidthyroid receptor.
 11. The method of claim 10 wherein said thyroidreceptor is TRα1.
 12. The method of claim 10 wherein said thyroidreceptor is TRβ1.
 13. The method of claim 10 wherein said compoundincreases mRNA expression of a gene selected from the group consistingof LDL receptor, ACC, FAS, spot-14, CPT-1, CYP7A, apo AI, and mGPDH. 14.The method of claim 1 or 2 wherein said compound reduces fat content inliver in the absence of any negative effects on the heart.
 15. Themethod of claim 14 wherein said negative effects include one or more ofsignificant increase in heart rate, significant raising of bloodpressure, significant increase in heart rate, significant increase inleft ventricular contractility, significant increase in systolic bloodpressure, and significant increase in diastolic blood pressure.
 16. Themethod of claim 1 or 2 wherein said compound reduces fat content inliver in the absence of any significant change in total body weight,significant change in TSH or TRH levels, significant change in liverenzymes, significant change in serum free fatty acid levels, orsignificant liver mitochondrial damage.
 17. The method of claim 1 or 2wherein said thyromimetic compound is administered in the form of apharmaceutical composition.
 18. The method of claim 17, wherein saidpharmaceutical composition is in the form of a controlled releasecomposition, transdermal patch, tablet, hard capsule, or soft capsule.19. The method of claim 1 or 2, wherein said thyromimetic compound isadministered orally in a unit dose of about 0.375 μg/kg to 3.375 mg/kg.20. The method of claim 1 or 2, wherein said thyromimetic compound isadministered orally in a total daily dose of about 0.375 μg/kg/day toabout 3.75 mg/kg/day, equivalent of the free acid.
 21. The method ofclaim 1 or 2, wherein said thyromimetic compound is a compound ofFormula I:(Ar¹)-G-(Ar²)-T-E wherein: Ar¹ and Ar² are substituted aryl groups; G isan atom or group of atoms that links Ar¹ and Ar² through a single C, S,Se, O, or N atom or CH₂ linked to C, S, Se, O, or N, wherein the C or Nis substituted; T is an atom or group of atoms linking Ar² to E through1-4 contiguous atoms or is absent; and E is a functional group or moietywith a pKa ≦7.4, a carboxylic acid or esters thereof, carboxylic acidamide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamicacid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylicacid surrogates, phosphonic acid, phosphonic acid monoester, phosphinicacid, or a prodrug thereof, or an atom or group of atoms containing an Oor N that binds the thyroid hormone binding pocket of a TRα or TRβ. 22.The method of claim 1 or 2, wherein said thyromimetic compound is acompound of Formula II:

wherein: G is selected from the group consisting of —O—, —S—, -Se-,—S(═O)—, —S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—,—CH(C₁-C₄ alkyl)-, CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups; or G is R⁵⁰-R⁵¹wherein; R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²) or alternatively R⁵⁰ andR⁵¹ are independently selected from O, S and —CH(R⁵³)—, with theprovisos that at least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰and R⁵¹ is O or S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; T is selected from the groupconsisting of —(CR^(a) ₂)_(k)—, —CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b)₂)(CR^(a) ₂)_(n)—, —S(CR^(b) ₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(b))C(O)(CR^(b) ₂)_(n)—, —(CR^(a)₂)_(m)C(R^(b))(NR^(b)R^(c))—, —C(O)(CR^(a) ₂)_(m)—, —(CR^(a)₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—S—(CR^(b) ₂)—(CR^(b) ₂)_(p)—, —(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a)₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—O—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a) ₂)—; k is aninteger from 0-4; m is an integer from 0-3; n is an integer from 0-2; pis an integer from 0-1; Each R^(a) is independently selected from thegroup consisting of hydrogen, optionally substituted —C₁-C₄ alkyl,halogen, —OH, optionally substituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂,—OCH₂F, optionally substituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionallysubstituted —C₂-C₄ alkenyl, and optionally substituted —C₂-C₄ alkynyl;with the proviso that when one R^(a) is attached to C through an O, S,or N atom, then the other R^(a) attached to the same C is a hydrogen, orattached via a carbon atom; Each R^(b) is independently selected fromthe group consisting of hydrogen and optionally substituted —C₁-C₄alkyl; Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H; R¹, R², R⁶, and R⁷ are each independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃ alkyl,optionally substituted —C₂-C₄ alkenyl, optionally substituted —C₂-C₄alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —O—C₁-C₃ alkyl, hydroxy and cyano; or R⁶ and T are takentogether along with the carbons they are attached to form a ring of 5 to6 atoms with 0-2 unsaturations, not including the unsaturation on thering to which R⁶ and T are attached, and 0 to 2 heteroatomsindependently selected from —NR^(i)—, —O—, and —S—, with the provisothat when there are 2 heteroatoms in the ring and both heteroatoms aredifferent than nitrogen then both heteroatoms have to be separated by atleast one carbon atom; and X is attached to this ring by a direct bondto a ring carbon, or by —(CR^(a) ₂)— or —C(O)— bonded to a ring carbonor a ring nitrogen; R^(i) is selected from the group consisting ofhydrogen, —C(O)C₁-C₄ alkyl, —C₁-C₄ alkyl, and —C₁-C₄-aryl; or R¹ and R⁷are taken together along with the carbons to which they are attached toform an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R¹and R⁷ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, hydroxy, —(CR^(a)₂)aryl, —(CR^(a) ₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl,—C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano; R³ and R⁴are each independently selected from the group consisting of hydrogen,halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano, optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl,—C(R^(b))═C(R^(b))— cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl,—C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a)₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h),—C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(═O)₂R^(c), —N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); EachR^(d) is selected from the group consisting of optionally substituted—C₂-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionally substituted—(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) isselected from the group consisting of optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, —CHF₂, —CH₂F, optionally substituted phenyl, and —C(O)OR^(h); EachR^(h) is selected from the group consisting of optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl; or R³ and R⁸ are takentogether along with the carbon atoms to which they are attached to forman optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations,not including the unsaturation on the ring to which R³ and R⁸ areattached, including 0 to 2 heteroatoms independently selected from—NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;or R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring comprising—CH═CH—CH═, —N═CH—CH═, —CH═N—CH— or —CH═CH—N═; R⁵ is selected from thegroup consisting of —OH, optionally substituted —OC₁-C₆ alkyl,—OC(O)R^(e), —OC(O)OR^(h), NHC(O)Olh, —OC(O)NH(R^(h)), —F, —NHC(O)R^(e),—NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h));or R³ and R⁵ are taken together along with the carbons they are attachedto form an optionally substituted ring of 5 to 6 atoms with 0-2unsaturations, not including the unsaturation on the ring to which R³and R⁵ are attached, including 0 to 2 heteroatoms independently selectedfrom —NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;and X is carboxylic acid or esters thereof, carboxylic acid amide,sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid,or a prodrug thereof.
 23. The method of claim 1 or 2, wherein saidthyromimetic compound is a compound of Formula III:

wherein: G is selected from the group consisting of —O—, —S—, -Se-,—S(═O)—, —S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—,—CH(C₁-C₄ alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups; or G is R⁵⁰-R⁵¹wherein; R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ andR⁵¹ are independently selected from O, S and —CH(R⁵³)—, with theprovisos that at least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰and R⁵¹ is O or S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; T is selected from the groupconsisting of —(CR^(a) ₂)_(k)—, —CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b)₂)(CR^(a) ₂)_(n)—, —S(CR^(b) ₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(m)C(R^(b))(NR^(b)R^(c))—, —C(O)(CR^(a) ₂)_(m)—, —(CR^(a)₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a)₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—O—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—N(R^(c))—(CR^(b) ₂) and —(CH₂)_(p)C(O)N(R^(b))C(R^(a) ₂)—; k is aninteger from 0-4; m is an integer from 0-3; n is an integer from 0-2; pis an integer from 0-1; Each R^(a) is independently selected from thegroup consisting of hydrogen, optionally substituted —C₁-C₄ alkyl,halogen, —OH, optionally substituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂,—OCH₂F, optionally substituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionallysubstituted —C₂-C₄ alkenyl, and optionally substituted —C₂-C₄ alkynyl;with the proviso that when one R^(a) is attached to C through an O, S,or N atom, then the other R^(a) attached to the same C is a hydrogen, orattached via a carbon atom; Each R^(b) is independently selected fromthe group consisting of hydrogen and optionally substituted —C₁-C₄alkyl; Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H; R¹ and R² are each independently selectedfrom the group consisting of hydrogen, halogen, optionally substituted—C₁-C₄ alkyl, optionally substituted —S—C₁-C₃ alkyl, optionallysubstituted —C₂-C₄ alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃,—CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃alkyl, and cyano; with the proviso that at least one of R¹ and R² is nothydrogen; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂,—OCH₂F, cyano, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(a) ₂)_(m)aryl, optionally substituted—(CR^(a) ₂)_(m)cycloalkyl, optionally substituted —(CR^(a)₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))—cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl),—C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b)₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e),N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); Each R^(d) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted —(CR^(b) ₂)_(n)cycloalkyl, optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, —CHF₂, —CH₂F, optionally substituted phenyl, and —C(O)OR^(h); EachR^(h) is selected from the group consisting of optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl; R⁵ is selected from thegroup consisting of —OH, optionally substituted —OC₁-C₆ alkyl,—OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h), —OC(O)NH(R^(h)), —F,—NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and—NHC(O)NH(R^(h)); or R³ and R⁵ are taken together along with the carbonsthey are attached to form an optionally substituted ring of 5 to 6 atomswith 0-2 unsaturations, not including the unsaturation on the ring towhich R³ and R⁵ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom; and X is carboxylic acid or esters thereof, carboxylic acidamide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamicacid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylicacid surrogates, phosphonic acid, phosphonic acid monoester, phosphinicacid, or a prodrug thereof.
 24. The method of claim 1 or 2, wherein saidthyromimetic compound is a compound of Formula IV:

wherein: A is selected from the group consisting of —NR^(i)—, —O—, and—S—; B is selected from the group consisting of —CR^(b)—, and —N—; R^(i)is selected from the group consisting of hydrogen, —C(O)C₁-C₄ alkyl,—C₁-C₄ alkyl, and —C₁-C₄-aryl; R^(b) is selected from the groupconsisting of hydrogen and optionally substituted —C₁-C₄ alkyl; G isselected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O)₂—,—CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C₁-C₄ alkyl)-, orCH₂ linked to any of the preceding groups; or G is R⁵⁰-R⁵¹ wherein;R⁵⁰-R⁵¹ together are —C⁵²)═C(R⁵²)— or alternatively R⁵⁰ and R⁵¹ areindependently selected from O, S and —CH(R⁵³)—, with the provisos thatat least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰ and R⁵¹ is Oor S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; D is selected from the groupconsisting of a bond, —(CR^(a) ₂)—, and —C(O)—; n is an integer from0-2; Each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl, with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom; R¹ and R² are each independently selected from the groupconsisting of halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano; R³ andR⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))— cycloalkyl,—C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),—SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e),—N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); Each R^(d) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted —(CR^(b) ₂)_(n)cycloalkyl, optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₂-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, which may contain a second heterogroupselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h); Each R^(h) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted —(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(b) ₂)_(n)heterocycloalkyl; R⁵ is selected from the groupconsisting of —OH, optionally substituted —OC₁-C₆ alkyl, —OC(O)R^(e),—OC(O)OR^(h), —NHC(O)OR^(h), OC(O)NH(R^(h)), —F, —NHC(O)R^(e),—NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h));and X is carboxylic acid or esters thereof, carboxylic acid amide,sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid,or a prodrug thereof.
 25. The method of claim 1 or 2, wherein saidthyromimetic compound is a compound of Formula V:

wherein: G is selected from the group consisting of —O—, —S—, -Se-,—S(═O)—, —S(═O)₂—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —NH—, and—N(C₁-C₄ alkyl)-, or CH₂ linked to any of the preceding groups; or G isR⁵⁰-R⁵¹ wherein; R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternativelyR⁵⁰ and R⁵¹ are independently selected from O, S and —CH(R⁵³)—, with theprovisos that at least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰and R⁵¹ is O or S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; T is selected from the groupconsisting of —(CR^(a) ₂)_(k)—, —CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(n)—CR^(b)═CR^(b)—, (CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b)₂)(CR^(a) ₂)_(n)—, —S(CR^(b) ₂)(CR^(a) ₂)_(n), —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(m)C(R^(b))(NR^(b)R^(c))—, —C(O)(CR^(a) ₂)_(m)—, —(CR^(a)₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—N(CR^(b) ₂)—S—(CR^(b)₂)—(CR^(a) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—O—(CR^(b) ₂)—), —(CR^(a)₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a) ₂)—; k is aninteger from 0-4; m is an integer from 0-3; n is an integer from 0-2; pis an integer from 0-1; Each R^(a) is independently selected from thegroup consisting of hydrogen, optionally substituted —C₁-C₄ alkyl,halogen, —OH, optionally substituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂,—OCH₂F, optionally substituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionallysubstituted —C₂-C₄ alkenyl, and optionally substituted —C₂-C₄ alkynyl;with the proviso that when one R^(a) is attached to C through an O, S,or N atom, then the other R^(a) attached to the same C is a hydrogen, orattached via a carbon atom; Each R^(b) is independently selected fromthe group consisting of hydrogen and optionally substituted —C₁-C₄alkyl; Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H; R¹ and R² are each independently selectedfrom the group consisting of halogen, optionally substituted —C₁-C₄alkyl, optionally substituted —S—C₁-C₃ alkyl, optionally substituted—C₂-C₄ alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, andcyano; R⁸ is selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃alkyl, optionally substituted —C₂-C₄ alkenyl, optionally substituted—C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF2, —OCH₂F, optionallysubstituted —O—C₁-C₃ alkyl, hydroxy, —(CR^(a) ₂)aryl, —(CR^(a)₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl,—C(O)heterocycloalkyl, —C(O)alkyl and cyano; R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, halogen,—CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(m)aryl,optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionally substituted—(CR^(a) ₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl,—C(R^(b))═C(R^(b))— cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl,—C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a)₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂N^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h),—C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(O)₂R^(e), —N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); EachR^(d) is selected from the group consisting of optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionally substituted—(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) isselected from the group consisting of optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, which may contain a second heterogroupselected from the group consisting of O, NR^(c), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, —CHF₂, —CH₂F,optionally substituted phenyl, and —C(O)OR^(h); Each R^(h) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted —(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(b) ₂)_(n)heterocycloalkyl; R³ and R⁸ are taken together along withthe carbon atoms to which they are attached to form an optionallysubstituted ring of 5 to 6 atoms with 0-2 unsaturations, not includingthe unsaturation on the ring to which R³ and R⁸ are attached, including0 to 2 heteroatoms independently selected from —NR—, —O—, and —S—, withthe proviso that when there are 2 heteroatoms in the ring and bothheteroatoms are different than nitrogen then both heteroatoms have to beseparated by at least one carbon atom; or R⁸ and G are taken togetheralong with the carbon atoms to which they are attached to form anoptionally substituted ring comprising —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═or —CH═CH—N═; R⁵ is selected from the group consisting of —OH,optionally substituted —OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h),—NHC(O)OR^(h), —OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e),—NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or R³ and R⁵are taken together along with the carbons they are attached to form aring of 5 to 6 atoms with 0-2 unsaturations, not including theunsaturation on the ring to which R³ and R⁵ are attached, including 0 to2 heteroatoms independently selected from —NR^(i)—, —O—, and —S—, withthe proviso that when there are 2 heteroatoms in the ring and bothheteroatoms are different than nitrogen then both heteroatoms have to beseparated by at least one carbon atom; R⁷ is selected from the groupconsisting of hydrogen, halogen, amino, hydroxyl, —O—C₁-C₄ alkyl, —OCF₃,—OCHF₂, —OCH₂F, —CF₃, —CHF₂, —CH₂F, cyano, —SH and —S—C₁-C₄ alkyl; and Xis carboxylic acid or esters thereof, carboxylic acid amide, sulfonicacid, tetrazole, hydroxamic acid, oxamic acid, malonamnic acid,6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acidsurrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid,or a prodrug thereof.
 26. The method of claim 1 or 2, wherein saidthyromimetic compound is a compound of Formula VI:

wherein: T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b)—(CR₂)_(n)—, —(CR^(a) ₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a)₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—, —S(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—,—N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(m)C(R^(b))(NR^(b)R^(c))—,—C(O)(CR^(a) ₂)_(m)—, (CR^(a) ₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b)₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—O—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a)₂)—; k is an integer from 0-4; m is an integer from 0-3; n is an integerfrom 0-2; p is an integer from 0-1; Each R^(a) is independently selectedfrom the group consisting of hydrogen, optionally substituted —C₁-C₄alkyl, halogen, —OH, optionally substituted —O—C₁-C₄ alkyl, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —S—C₁-C₄ alkyl, —NR^(b)R^(c),optionally substituted —C₂-C₄ alkenyl, and optionally substituted —C₂-C₄alkynyl; with the proviso that when one R^(a) is attached to C throughan O, S, or N atom, then the other R^(a) attached to the same C is ahydrogen, or attached via a carbon atom; Each R^(b) is independentlyselected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl; Each R^(c) is independently selected from thegroup consisting of hydrogen and optionally substituted —C₁-C₄ alkyl,optionally substituted —C(O)—C₁-C₄ alkyl, and —C(O)H; R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,optionally substituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃alkyl, optionally substituted —C₂-C₄ alkenyl, optionally substituted—C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —O—C₁-C₃ alkyl, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen; R³ is selected from the groupconsisting of hydrogen, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂,—OCH₂F, cyano, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(a) ₂)_(m)aryl, optionally substituted—(CR^(a) ₂)_(m)cycloalkyl, optionally substituted —(CR^(a)₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))—cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl),—C≡C(cycloalkyl), C≡C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b)₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e),—N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂N^(f)R^(g), and —NR^(f)R^(g); Each R^(d) is selected fromthe group consisting of optionally substituted —C₁-C₁₂ alky, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂akynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂),aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, optionally substituted phenyl, and —C(O)OR^(h); Each R^(h) isselected from the group consisting of optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted -(Cle2),cycloalkyl, and optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl; R⁵ is selected from the group consisting of —OH,optionally substituted —OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h),—NHC(O)OR^(h), —OC(O)NH(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e),—NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); and X iscarboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid,tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil,thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates,phosphonic acid, phosphonic acid monoester, phosphinic acid, or aprodrug thereof.
 27. The method of claim 1 or 2, wherein saidthyromimetic compound is a compound of Formula VII:

wherein: G is selected from the group consisting of —O—, —S—, -Se-,—S(═O)—, —S(═O)₂—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —NH—, and—N(C₁-C₄ alkyl)-, or CH₂ linked to any of the preceding groups; or G isR⁵⁰-R⁵¹ wherein; R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternativelyR⁵⁰ and R⁵¹ are independently selected from O, S and —CH(R⁵³)—, with theprovisos that at least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰and R⁵¹ is O or S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₂-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; T is selected from the groupconsisting of —(CR^(a) ₂)_(k)—, —CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b)₂)(CR^(a) ₂)_(n)—, —S(CR^(b) ₂)(CR^(a) ₂)_(n)—, —N(R^(c))(CR^(b)₂)(CR^(a) ₂)_(n)—, —N(R^(b))C(O)(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(m)C(R^(b))(NR^(b)R^(c))—, —C(O)(CR^(a) ₂)_(m)—, —(CR^(a)₂)_(m)C(O)—, —(CR^(b) ₂)—O—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b)₂)—S—(CR^(b) ₂)—(CR^(a) ₂)_(p)—, —(CR^(b) ₂)—N(R^(c))—(CR^(b) ₂)—(CR^(a)₂)_(p)—, —(CR^(a) ₂)_(p)—(CR^(b) ₂)—O—(CR^(b) ₂)—, —(CR^(a)₂)_(p)—(CR^(b) ₂)—S—(CR^(b) ₂)—, —(CR^(a) ₂)_(p)—(CR^(b)₂)—N(R^(c))—(CR^(b) ₂)— and —(CH₂)_(p)C(O)N(R^(b))C(R^(a) ₂)—; k is aninteger from 0-4; m is an integer from 0-3; n is an integer from 0-2; pis an integer from 0-1; Each R^(a) is independently selected from thegroup consisting of hydrogen, optionally substituted —C₁-C₄ alkyl,halogen, —OH, optionally substituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂,—OCH₂F, optionally substituted —S—C₁-C₄ alkyl, —NR^(b)R^(c), optionallysubstituted —C₂-C₄ alkenyl, and optionally substituted —C₂-C₄ alkynyl;with the proviso that when one R^(a) is attached to C through an O, S,or N atom, then the other R^(a) attached to the same C is a hydrogen, orattached via a carbon atom; Each R^(b) is independently selected fromthe group consisting of hydrogen and optionally substituted —C₁-C₄alkyl; Each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H; R¹ and R² are each independently selectedfrom the group consisting of hydrogen, halogen, optionally substituted—C₁-C₄ alkyl, optionally substituted —S—C₁-C₃ alkyl, optionallysubstituted —C₂-C₄ alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃,—CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃alkyl, and cyano; with the proviso that at least one of R¹ and R² is nothydrogen; R³ is selected from the group consisting of hydrogen, halogen,—CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(m)aryl,optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionally substituted—(CR^(a) ₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl,—C(R^(b))═C(R^(b))— cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl,—C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a)₂)_(n)(CR^(b) ₂)_(f)R⁹, —OR^(d), —SR^(d), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h), —C(O)R^(e),—N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); Each R^(d) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted —(CR^(b) ₂)ncycloalkyl, optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, —CHF₂, —CH₂F, optionally substituted phenyl, and —C(O)OR^(h); EachR^(h) is selected from the group consisting of optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl; R⁵ is selected from thegroup consisting of —OH, optionally substituted —OC₁-C₆ alkyl,—OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h), —OC(O)NH(R^(h)), —F,—NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and—NHC(O)NH(R^(h)); or R³ and R⁵ are taken together along with the carbonsthey are attached to form an optionally substituted ring of 5 to 6 atomswith 0-2 unsaturations, not including the unsaturation on the ring towhich R³ and R⁵ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom; R⁹ is selected from the group consisting of hydrogen,halogen, optionally substituted —C₁-C₄ alkyl, optionally substituted—S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl, optionallysubstituted —C₂-C₄ alkynyl, —CF₃, —OCF₃, optionally substituted-O—C₁-C₃alkyl, hydroxy, (CR^(a) ₂)aryl, C(O)aryl, C(O)alkyl and cyano; and X iscarboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid,tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil,thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates,phosphonic acid, phosphonic acid monoester, phosphinic acid, or aprodrug thereof.
 28. The method of claim 1 or 2, wherein saidthyromimetic compound is a compound of Formula VIII:

wherein: G is selected from the group consisting of —O—, —S—, -Se-,—S(═O)—, —S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—,—CH(C₁-C₄ alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(—CH₂)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups; or G is R⁵⁰-R⁵¹wherein; R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ andR⁵¹ are independently selected from O, S and —CH(R⁵³)—, with theprovisos that at least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰and R⁵¹ is O or S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; A and T are eachindependently selected from the group consisting of —(CR^(a) ₂)—,—(CR^(a) ₂)₂—, —O(CR^(b) ₂)—, —S(CR^(b) ₂)—, —N(R^(c))(CR^(b) ₂)—,—N(R^(b))C(O)—, —C(O)(CR^(a) ₂)—, —(CR^(a) ₂)C(O)—, —(CR^(b) ₂)O—,—(CR^(b) ₂)S—, and —(CR^(b) ₂)N(R^(c))—; Each R^(a) is independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₄ alkyl, halogen, —OH, optionally substituted —O—C₁-C₄ alkyl,—OCF₃, —OCHF₂, —OCH₂F, optionally substituted —S—C₁-C₄ alkyl,—NR^(b)R^(c), optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R^(a) isattached to C through an O, S, or N atom, then the other R^(a) attachedto the same C is a hydrogen, or attached via a carbon atom; Each R^(b)is independently selected from the group consisting of hydrogen andoptionally substituted —C₁-C₄ alkyl; Each R^(c) is independentlyselected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl, and—C(O)H; R¹, R², and R⁷, are each independently selected from the groupconsisting of hydrogen, halogen, optionally substituted —C₁-C₄ alkyl,optionally substituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, and cyano;with the proviso that at least one of R¹ and R² is not hydrogen; R⁸ andR⁹ are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted —C₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, optionally substituted —O—C₁-C₃ alkyl, hydroxy, —(CR^(a)₂)aryl, —(CRhu a₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl,—C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano; R³ and R⁴are each independently selected from the group consisting of hydrogen,halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano, optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(m)heterocycloalkyl, —C(R^(b))═C(R^(b))-aryl,—C(R^(b))═C(R^(b))—cycloalkyl, —C(R^(b))═C(R^(b))-heterocycloalkyl,—C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR^(a)₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d), —SR^(d), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g), —C(O)OR^(h),—C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(═O)₂R^(e), —N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); EachR^(d) is selected from the group consisting of optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, optionally substituted—(CR^(b) ₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) isselected from the group consisting of optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(e) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, —CHF₂, —CH₂F, optionally substituted phenyl, and —C(O)OR^(h); EachR^(h) is selected from the group consisting of optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl; R³ and R⁸ are takentogether along with the carbon atoms to which they are attached to forman optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations,not including the unsaturation on the ring to which R³ and R⁸ areattached, including 0 to 2 heteroatoms independently selected from—NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;or R⁸ and G are taken together along with the carbon atoms to which theyare attached to form an optionally substituted ring of formula—CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═; R⁵ is selected from thegroup consisting of —OH, optionally substituted —OC₁-C₆ alkyl,—OC(O)R^(e), —OC(O)OR^(h), —NHC(O)OR^(h), —OC(O)NH(R^(h)), —F,—NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and—NHC(O)NH(R^(h)); or R³ and R¹ are taken together along with the carbonsthey are attached to form an optionally substituted ring of 5 to 6 atomswith 0-2 unsaturations, not including the unsaturation on the ring towhich R³ and R⁵ are attached, including 0 to 2 heteroatoms independentlyselected from —NR^(h)—, —O—, and —S—, with the proviso that when thereare 2 heteroatoms in the ring and both heteroatoms are different thannitrogen then both heteroatoms have to be separated by at least onecarbon atom; Y is selected from the group consisting of —O—, and—NR^(v)—; when Y is —O—, R¹¹ attached to —O— is independently selectedfrom the group consisting of —H, alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substitutedCH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R^(z))₂OC(O)NR^(z)₂, —NR^(z)—C(O)—R^(y), —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y),—C(R^(z))₂OC(O)SR^(y), -alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; when Y is —NR^(v)—, then R¹¹ attached to—NR^(v)— is independently selected from the group consisting of —H,—[C(R^(z))₂]_(q)—C(O)OR^(y), —C(R^(x))₂C(O)OR^(y),—[C(R^(z))₂]_(q)—C(O)SR^(y), and -cycloalkylene-C(O)OR^(y); q is aninteger 2 or 3; Each R^(z) is selected from the group consisting ofR^(y) and —H; Each R^(y) is selected from the group consisting of alkyl,aryl, heterocycloalkyl, and aralkyl; Each R^(x) is independentlyselected from the group consisting of —H, and alkyl, or together R^(x)and R^(x) form a cycloalkyl group; Each R^(V) is selected from the groupconsisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, andlower acyl; and pharmaceutically acceptable salts and prodrugs thereofand pharmaceutically acceptable salts of said prodrugs.
 29. The methodof claim 1 or 2, wherein said thyromimetic compound is a compound ofFormula IX:

wherein: G is selected from the group consisting of —O—, —S—, -Se-,—S(═O)—, —S(═O)₂—, -Se-, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—,—CH(C₁-C₄ alkyl)-, —CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄alkyl)-, or CH₂ linked to any of the preceding groups; or G is R⁵⁰-R⁵¹wherein; R⁵⁰-R⁵¹ together are —C(R⁵²)═C(R⁵²)— or alternatively R⁵⁰ andR⁵¹ are independently selected from O, S and —CH(R⁵³)—, with theprovisos that at least one R⁵⁰ and R⁵¹ is —CH(R⁵³)—, and when one of R⁵⁰and R⁵¹ is O or S, then R⁵³ is R⁵⁴; R⁵⁴ is hydrogen, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, fluoromethyl, difluoromethyl, ortrifluoromethyl; R⁵³ is selected from hydrogen, halogen, hydroxyl,mercapto, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; R⁵² is selected fromhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio,difluoromethylthio and trifluoromethylthio; T is selected from the groupconsisting of —(CR^(a) ₂)_(n)C(R^(b) ₂)O—, —(CR^(a) ₂)_(n)C(R^(b)₂)N(R^(b))—, —(CR^(a) ₂)_(n)C(R^(b) ₂)S—, —C(O)(CR^(a) ₂)_(p)C(R^(b)₂)O—, —C(O)(CR^(a) ₂)_(p)C(R^(b) ₂)N(R^(b))—, —C(O)(CR^(a) ₂)_(p)C(R^(b)₂)S—, —(CR^(a) ₂)_(p)C(O)C(R^(b) ₂)O—, —(CR^(a) ₂)_(p)C(O)C(R^(b)₂)N(R^(b))—, and —(CR^(a) ₂)_(p)C(O)C(R^(b) ₂)S—, k is an integer from0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integerfrom 0-1; Each R^(a) is independently selected from the group consistingof hydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH,optionally substituted —O—C₁-C₄ alkyl, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —S—C₁-C₄ alkyl, —NR^(b)R^(c)C, optionally substituted —C₂-C₄alkenyl, and optionally substituted —C₂-C₄ alkynyl; with the provisothat when one R^(a) is attached to C through an O, S, or N atom, thenthe other R^(a) attached to the same C is a hydrogen, or attached via acarbon atom; Each R^(b) is independently selected from the groupconsisting of hydrogen and optionally substituted —C₁-C₄ alkyl; EachR^(c) is independently selected from the group consisting of hydrogenand optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H; R¹, R², R⁶, and R⁷ are each independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃ alkyl,optionally substituted —C₂-C₄ alkenyl, optionally substituted —C₂-C₄alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted —O—C₁-C₃ alkyl, and cyano; with the proviso that at leastone of R¹ and R² is not hydrogen; R⁸ and R⁹ are each independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted —C₁-C₄ alkyl, optionally substituted —S—C₁-C₃ alkyl,optionally substituted —C₂-C₄ alkenyl, optionally substituted —C₂-C₄alkynyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, optionallysubstituted-O—C₁-C₃ alkyl, hydroxy, —(CR^(a) ₂)aryl, —(CR^(a)₂)cycloalkyl, —(CR^(a) ₂)heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl,—C(O)heterocycloalkyl, —C(O)alkyl and cyano; or R¹ and R⁷ are takentogether along with the carbon atoms to which they are attached to forman optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations,not including the unsaturation on the ring to which R¹ and R⁷ areattached, including 0 to 2 heteroatoms independently selected from—NR^(h)—, —O—, and —S—, with the proviso that when there are 2heteroatoms in the ring and both heteroatoms are different than nitrogenthen both heteroatoms have to be separated by at least one carbon atom;R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CH₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, cyano,optionally substituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂alkenyl, optionally substituted —C₂-C₁₂ alkynyl, optionally substituted—(CR^(a) ₂)_(m)aryl, optionally substituted —(CR^(a) ₂)_(m)cycloalkyl,optionally substituted —(CR^(a) ₂)_(m)heterocycloalkyl,—C(R^(b))═C(R^(b))-aryl, —C(R^(b))═C(R^(b))— cycloalkyl,—C(R^(b))═C(R^(b))-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl),—C≡-C(heterocycloalkyl), —(CR^(a) ₂)_(n)(CR^(b) ₂)NR^(f)R^(g), —OR^(d),SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(—O)₂NR^(f)R^(g), —C(O)NR^(f)R^(g),—C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g),—N(R^(b))S(═O)₂NR^(f)R^(g), —N(R^(h))S(═O)₂R^(e),—(R^(b))S(═O)₂NR^(f)N^(g), and —NR^(f)R^(g); Each R^(d) is selected fromthe group consisting of optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted—(CR^(b) ₂)_(n)cycloalkyl, optionally substituted —(CR^(b)₂)_(n)heterocycloalkyl, and —C(O)NR^(f)R^(g); Each R^(e) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(a) ₂)_(n)aryl, optionallysubstituted —(CR^(a) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n)heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl,optionally substituted —(CR^(b) ₂)_(n)cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring of 3-8 atomscontaining 0-4 unsaturations, said heterocyclic ring may contain asecond heterogroup within the ring selected from the group consisting ofO, NR^(c), and S, wherein said optionally substituted heterocyclic ringmay be substituted with 0-4 substituents selected from the groupconsisting of optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano,—CF₃, optionally substituted phenyl, and —C(O)OR^(h); Each R^(h) isselected from the group consisting of optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionallysubstituted —(CR^(b) ₂)_(n)cycloalkyl, and optionally substituted—(CR^(b) ₂)_(n)heterocycloalkyl; or R³ and R⁸ are taken together alongwith the carbon atoms to which they are attached to form an optionallysubstituted ring of 5 to 6 atoms with 0-2 unsaturations, not includingthe unsaturation on the ring to which R³ and R¹ are attached, including0 to 2 heteroatoms independently selected from —NR^(h)—, —O—, and —S—,with the proviso that when there are 2 heteroatoms in the ring and bothheteroatoms are different than nitrogen then both heteroatoms have to beseparated by at least one carbon atom; or R⁸ and G are taken togetheralong with the carbon atoms to which they are attached to form anoptionally substituted ring of formula —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═or —CH═CH—N═; R⁵ is selected from the group consisting of —OH,optionally substituted —OC₁-C₆ alkyl, —OC(O)R^(e), —OC(O)OR^(h),—NHC(O)OR^(h), —OC(O)N—H(R^(h)), —F, —NHC(O)R^(e), —NHS(═O)R^(e),—NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); or R³ and R⁵are taken together along with the carbons they are attached to form anoptionally substituted ring of 5 to 6 atoms with 0-2 unsaturations notincluding the unsaturation on the ring to which R³ and R⁵ are attached,including 0 to 2 heteroatoms independently selected from —NR^(h)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom; X is P(O)(YR¹¹)Y″; Y″is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionally substituted(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e), —(CR^(a)₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)N^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), and —(CR^(a) ₂)_(k)C(O)R^(e); Y is selected fromthe group consisting of —O—, and —NR^(v)—; when Y is —O—, R¹¹ attachedto —O— is independently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; when Y is —NR^(v)—, then R¹¹ attached to—NR^(v)— is independently selected from the group consisting of —H,—[C(R^(z))₂]_(q)—C(O)OR^(y), —C(R^(x))₂C(O)OR^(y),—[C(R^(z))₂]_(q)—C(O)SR^(y), and -cycloalkylene-C(O)OR^(y); q is aninteger 2 or 3; Each R^(z) is selected from the group consisting ofR^(y) and —H; Each R^(y) is selected from the group consisting of alkyl,aryl, heterocycloalkyl, and aralkyl; Each R^(x) is independentlyselected from the group consisting of —H, and alkyl, or together R^(x)and R^(x) form a cycloalkyl group; Each R^(v) is selected from the groupconsisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, andlower acyl; and pharmaceutically acceptable salts and prodrugs thereofand pharmaceutically acceptable salts of said prodrugs.
 30. The methodof any one of claims 22-29, wherein: X is P(O)(YR¹¹)(Y′R¹¹) orP(O)(YR¹¹)Y″; Y″ is selected from the group consisting of hydrogen,optionally substituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH,optionally substituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆alkynyl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionallysubstituted (CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e),—(CR^(a) ₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), and —(CR^(a) ₂)_(k)C(O)R^(e);; Y and Y′ are eachindependently selected from the group consisting of —O—, and —NR^(v)—;when Y is —O— and Y″ is hydrogen, optionally substituted —C₁-C₆-alkyl,—CF₃, —CHF₂, —CH₂F, —CH₂OH, optionally substituted —C₂-C₆ alkenyl,optionally substituted —C₂-C₆ alkynyl, optionally substituted —(CR^(a)₂)_(n)cycloalkyl, optionally substituted —(CR^(a)₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e), —(CR^(a)₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), or —(CR^(a) ₂)_(k)C(O)R^(e), or when Y and Y′ areboth —O—, R¹¹ attached to —O— is independently selected from the groupconsisting of —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂,—NR^(z)—C(O)—R^(y), —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y),—C(R^(z))₂OC(O)SR^(y), -alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; when Y is —NR^(v)— and Y″ is hydrogen,optionally substituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH,optionally substituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆alkynyl, optionally substituted —(CR^(a) ₂)_(n)cycloalkyl, optionallysubstituted —(CR^(a) ₂)_(n)heterocycloalkyl, —(CR^(a) ₂)_(k)S(═O)R^(e),—(CR^(a) ₂)_(k)S(═O)₂R^(e), —(CR^(a) ₂)_(k)S(═O)₂NR^(f)R^(g), —(CR^(a)₂)_(k)C(O)NR^(f)R^(g), or —(CR^(a) ₂)_(k)C(O)R^(e), or when Y and Y′ areboth —NR^(v)—, then R¹¹ attached to —NR^(v)— is independently selectedfrom the group consisting of —H, —[C(R^(z))₂]_(q)—C(O)OR^(y),—C(R^(x))₂C(O)OR^(y), —[C(R^(z))₂], —C(O)SR^(y), and-cycloalkylene-C(O)OR^(y); when Y is —O— and Y₁ is NR^(v), then R¹¹attached to —O— is independently selected from the group consisting of—H, alkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, optionally substituted CH₂-heterocycloakyl wherein thecyclic moiety contains a carbonate or thiocarbonate, optionallysubstituted -alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; and R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of —H, —[C(R^(z))₂]_(q)—C(O)OR^(y),(R^(x))₂C(O)OR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-C(O)OR^(y); or when Y and Y′ are independently selectedfrom —O— and —NR^(v)—, then R¹¹ and R¹¹ together form a cyclic groupcomprising -alkyl-S—S-alkyl-, or R¹¹ and R¹¹ together form the group:

wherein: V, W, and W′ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, heterocycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, optionally substituted I-alkenyl,and optionally substituted I-alkynyl; or together V and Z are connectedvia an additional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon,substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy,alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom thatis three atoms from both Y groups attached to the phosphorus; ortogether V and Z are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon or carbon substituted by hydrogen, that is fused to an arylgroup at the beta and gamma position to the Y attached to thephosphorus; or together V and W are connected via an additional 3 carbonatoms to form an optionally substituted cyclic group containing 6 carbonatoms or carbon substituted by hydrogen and substituted with onesubstituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy,attached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; Z is selected from the group consisting of—CHR^(z)OH, —CHR^(z)OC(O)R^(y), —CHR^(z)OC(S)R^(y), —CHR^(z)OC(S)OR^(y),—CHR^(z)OC(O)SR^(y), —CHR^(z)OCO₂R^(y), —OR^(z), —SR^(z), —CHR^(z)N₃,—CH₂aryl, —CH(aryl)OH, —CH(CH═CR^(z) ₂)OH, —CH(C≡C^(z))OH, —R^(z),—NR^(z) ₂, —OCOR^(y), —OCO₂R^(y), —SCOR^(y), —SCO₂R^(y), —NHCOR^(z),—NHCO₂R^(y), —CH₂NHaryl, —(CH₂)_(q)—OR^(z), and —(CH₂)_(q)—SR^(z); q isan integer 2 or 3; Each R^(z) is selected from the group consisting ofR^(y) and —H; Each R^(y) is selected from the group consisting of alkyl,aryl, heterocycloalkyl, and aralkyl; Each R^(x) is independentlyselected from the group consisting of —H, and alkyl, or together R^(x)and R^(x) form a cycloalkyl group; Each R^(v) is selected from the groupconsisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, andlower acyl; with the provisos that: a) V, Z, W, W′ are not all —H; andb) when Z is —R^(z), then at least one of V, W, and W′ is not —H, alkyl,aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts andprodrugs thereof and pharmaceutically acceptable salts of said prodrugs.31. The method of claim 1 or 2, wherein said compound is selected fromthe group consisting of:

and pharmaceutically acceptable salts thereof.
 32. The method of claim 1or 2, wherein said compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 33. The method of claim 1or 2, wherein said compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.